DRUGS & SUPPLEMENTS
Disfil usesDisfil consists of Aminohydroxybutyric Acid, Ectylurea, Phenobarbital, Phenytoin.
INDICATIONS AND USAGE
Disfil (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.
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 Disfil (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.
Prolonged therapy with barbiturates should be accompanied by periodic laboratory evaluation of organ systems, including hematopoietic, renal, and hepatic systems.
Most reports of clinically significant drug interactions occurring with the barbiturates have involved Disfil (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.
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
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.
Caution should be exercised when Disfil (Phenobarbital) is administered to a nursing woman, because small amounts of barbiturates are excreted in the milk.
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 Disfil (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 Disfil (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 Disfil (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 Disfil (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 Disfil (Phenobarbital) use
DRUG ABUSE AND DEPENDENCE
Controlled Substance – Disfil (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 Disfil (Phenobarbital) for each 100- to 200-mg dose of barbiturate that the patient has been taking. The total daily amount of Disfil (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 Disfil (Phenobarbital) may be administered IM in addition to the oral dose. After stabilization on Disfil (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 Disfil (Phenobarbital), 3 to 10 mg/kg/day. After withdrawal symptoms (hyperactivity, disturbed sleep, tremors, and hyperreflexia) are relieved, the dosage of Disfil (Phenobarbital) should be gradually decreased and completely withdrawn over a 2-week period.
Signs and Symptoms – The onset of symptoms following a toxic oral exposure to Disfil (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 Disfil (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 Disfil (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 Disfil (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 Disfil (Phenobarbital) must be individualized with full knowledge of its particular characteristics. Factors of consideration are the patient’s age, weight, and condition.
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 Disfil (Phenobarbital) should be administered during a 24-hour period.
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 Disfil (Phenobarbital) in the serum. To achieve the blood levels considered therapeutic in pediatric patients, higher per-kilogram dosages are generally necessary for Disfil (Phenobarbital) and most other anticonvulsants. In children and infants, Disfil (Phenobarbital) at a loading dose of 15 to 20 mg/kg produces blood levels of about 20 mcg/mL shortly after administration.
Disfil (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.
Disfil (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:
Disfil (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:
Disfil (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:
Disfil (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:
Huntsville, AL 35811
Disfil (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 Disfil (Phenytoin) sodium capsule, USP contains 100 mg Disfil (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 Disfil (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
Disfil (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, Disfil (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. Disfil (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 Disfil (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 Disfil (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 Disfil (Phenytoin).
In most patients maintained at a steady dosage, stable Disfil (Phenytoin) serum levels are achieved. There may be wide interpatient variability in Disfil (Phenytoin) serum levels with equivalent dosages. Patients with unusually low levels may be noncompliant or hypermetabolizers of Disfil (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 Disfil (Phenytoin) plasma levels, despite standard doses, presents a difficult clinical problem. Serum level determinations in such patients may be particularly helpful. As Disfil (Phenytoin) is highly protein bound, free Disfil (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 Disfil (Phenytoin) and its metabolites occurs partly with glomerular filtration but more importantly by tubular secretion. Because Disfil (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.
Patients with Renal or Hepatic Disease: Due to an increased fraction of unbound Disfil (Phenytoin) in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total Disfil (Phenytoin) plasma concentrations should be made with caution. Unbound Disfil (Phenytoin) concentrations may be more useful in these patient populations.
Age: Disfil (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). Disfil (Phenytoin) dosing requirements are highly variable and must be individualized.
Gender and Race: Gender and race have no significant impact on Disfil (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 Disfil (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.
Disfil (Phenytoin) serum level determinations may be necessary for optimal dosage adjustments.
Disfil (Phenytoin), USP is contraindicated in those patients with a history of hypersensitivity to Disfil (Phenytoin), USP, its inactive ingredients, or other hydantoins.
Coadministration of extended Disfil (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.
Effects of Abrupt Withdrawal
Abrupt withdrawal of Disfil (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 Disfil (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 Disfil (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 Disfil (Phenytoin) treatment. The onset of symptoms is usually within 28 days, but can occur later. Extended Disfil (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 Disfil (Phenytoin). Consideration should be given to avoiding Disfil (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 Disfil (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 Disfil (Phenytoin) sodium should be discontinued if an alternative etiology for the signs or symptoms cannot be established.
Extended Disfil (Phenytoin) sodium and other hydantoins are contraindicated in patients who have experienced Disfil (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 Disfil (Phenytoin) sodium.
Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with extended Disfil (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 Disfil (Phenytoin) hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute hepatotoxicity, extended Disfil (Phenytoin) sodium should be immediately discontinued and not readministered.
Hematopoietic complications, some fatal, have occasionally been reported in association with administration of extended Disfil (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 Disfil (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 Disfil (Phenytoin) in patients with epilepsy has been associated with decreased bone mineral density (osteopenia, osteoporosis and osteomalacia) and bone fractures. Disfil (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 Disfil (Phenytoin) Serum Levels
Acute alcoholic intake may increase Disfil (Phenytoin) serum levels, while chronic alcohol use may decrease serum levels.
Exacerbation of Porphyria
In view of isolated reports associating Disfil (Phenytoin) with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease.
Usage In Pregnancy:
Prenatal exposure to Disfil (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 Disfil (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 Disfil (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 Disfil (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 Disfil (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.
Increased resorption and malformation rates have been reported following administration of Disfil (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.
The liver is the chief site of biotransformation of Disfil (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 Disfil (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. Disfil (Phenytoin) may also raise the serum glucose level in diabetic patients.
Disfil (Phenytoin) is not indicated for seizures due to hypoglycemic or other metabolic causes. Appropriate diagnostic procedures should be performed as indicated.
Disfil (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 Disfil (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 Disfil (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 Disfil (Phenytoin) sodium. Instruct patients to take extended Disfil (Phenytoin) sodium only as prescribed.
Patients taking Disfil (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 Disfil (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.
Disfil (Phenytoin) serum level determinations may be necessary to achieve optimal dosage adjustments. Disfil (Phenytoin) doses are usually selected to attain therapeutic plasma total Disfil (Phenytoin) concentrations of 10 to 20 mcg/mL (unbound Disfil (Phenytoin) concentrations of 1 to 2 mcg/mL).
Disfil (Phenytoin) is extensively bound to serum plasma proteins and is prone to competitive displacement. Disfil (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 Disfil (Phenytoin) concentrations and enhance the risk of drug toxicity. Disfil (Phenytoin) is a potent inducer of hepatic drug-metabolizing enzymes. Serum level determinations for Disfil (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 Disfil (Phenytoin) concentrations:
Drugs affected by Disfil (Phenytoin):
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 Disfil (Phenytoin) plasma levels. It is therefore suggested that Disfil (Phenytoin) not be administered concomitantly with an enteral feeding preparation. More frequent serum Disfil (Phenytoin) level monitoring may be necessary in these patients.
Drug/Laboratory Test Interactions:
Disfil (Phenytoin) may decrease serum concentrations of T4. It may also produce lower than normal values for dexamethasone or metyrapone tests. Disfil (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 Disfil (Phenytoin) concentrations.
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 Disfil (Phenytoin) sodium, physicians are advised to recommend that pregnant patients taking extended Disfil (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/.
Infant breast-feeding is not recommended for women taking this drug because Disfil (Phenytoin) appears to be secreted in low concentrations in human milk.
Pediatric Use: See DOSAGE AND ADMINISTRATION section.
Geriatric Use: Disfil (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 Disfil (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 Disfil (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 Disfil (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 Disfil (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.
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 Disfil (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 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 Disfil (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 Disfil (Phenytoin) sodium capsules, USP to Prompt Disfil (Phenytoin) Sodium Capsules, USP, and from the sodium salt to the free acid form.
Extended Disfil (Phenytoin) sodium capsules, USP are formulated with the sodium salt of Disfil (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.
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 Disfil (Phenytoin) and changes in dosage (increase or decrease) should not be carried out at intervals shorter than seven to ten days.
Patients who have received no previous treatment may be started on one 100-mg extended Disfil (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.
In adults, if seizure control is established with divided doses of three 100-mg extended Disfil (Phenytoin) sodium capsules, USP daily, once-a-day dosage with 300 mg of extended Disfil (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 Disfil (Phenytoin) sodium capsules, USP are recommended for once-a-day dosing. Inherent differences in dissolution characteristics and resultant absorption rates of Disfil (Phenytoin) due to different manufacturing procedures and/or dosage forms preclude such recommendation for other Disfil (Phenytoin) products. When a change in the dosage form or brand is prescribed, careful monitoring of Disfil (Phenytoin) serum levels should be carried out.
Some authorities have advocated use of an oral loading dose of Disfil (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 Disfil (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 Disfil (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 Disfil (Phenytoin) in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total Disfil (Phenytoin) plasma concentrations should be made with caution. Unbound Disfil (Phenytoin) concentrations may be more useful in these patient populations.
Elderly Patients: Disfil (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 Disfil (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.
SPL MEDGUIDE SECTION
Disfil pharmaceutical active ingredients containing related brand and generic drugs:
Active ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.
Disfil available forms, composition, doses:
Form of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.
Disfil destination | category:
Destination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.
Disfil Anatomical Therapeutic Chemical codes:
A medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.
Disfil pharmaceutical companies:
Pharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.
Frequently asked QuestionsCan i drive or operate heavy machine after consuming Disfil?
Depending on the reaction of the Disfil after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Disfil not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.Is Disfil addictive or habit forming?
Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.
Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.
Reviewsdrugs.com conducted a study on Disfil, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Disfil consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.
Visitor reported usefulNo survey data has been collected yet
Visitor reported side effectsNo survey data has been collected yet
Visitor reported price estimatesNo survey data has been collected yet
Visitor reported frequency of useNo survey data has been collected yet
Visitor reported dosesNo survey data has been collected yet
Visitor reported time for resultsNo survey data has been collected yet
Visitor reported administrationNo survey data has been collected yet
Visitor reported ageNo survey data has been collected yet
The information was verified by Dr. Arunabha Ray, MD Pharmacology