Dilantin

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 phenytoin plasma levels. It is therefore suggested that phenytoin not be administered concomitantly with an enteral feeding preparation.

More frequent serum phenytoin level monitoring may be necessary in these patients.

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

See Dosage.

The liver is the chief site of biotransformation of Dilantin (extended phenytoin sodium capsules). 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 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.

Toxic hepatitis, liver damage, and hypersensitivity syndrome have been reported and may, in rare cases, be fatal (see Adverse Effects).

Phenytoin should be discontinued if a skin rash appears (see Warnings regarding drug discontinuation). If the rash is exfoliative, purpuric, or bullous or if lupus erythematosus or Stevens-Johnson syndrome or toxic epidermal necrolysis is suspected, use of this drug should not be resumed and alternative therapy should be considered (see Adverse Effects). If the rash is of a milder type (measles-like or scarlatiniform), therapy may be resumed after the rash has completely disappeared. If the rash recurs upon reinstitution of therapy, further phenytoin medication is contraindicated.

Literature reports suggest that the combination of phenytoin, cranial irradiation and the gradual reduction of corticosteroids may be associated with the development of erythema multiforme, and/or Stevens-Johnson syndrome, and/or toxic epidermal necrolysis. In any of the above instances, caution should be exercised if using structurally similar compounds (e.g., barbiturates, succinimides, oxazolidinediones and other related compounds) in these same patients.

While macrocytosis and megaloblastic anemia have occurred, these conditions usually respond to folic acid therapy. If folic acid is added to phenytoin therapy, a decrease in seizure control may occur.

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

Osteomalacia has been associated with phenytoin therapy and is considered to be due to phenytoin's interference with vitamin D metabolism.

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

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 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 level determinations are recommended. Dose reduction of phenytoin therapy is indicated if plasma levels are excessive; if symptoms persist, termination is recommended (see Warnings).

See Warnings.

Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments.

See Warnings.

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

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

Patients should be instructed to call their physician if skin rash develops.

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

Do not use capsules which are discolored.

Phenytoin may cause decreased serum levels of protein-bound iodine (PBI). It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may cause increased serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT). Phenytoin may affect blood calcium and blood sugar metabolism tests.

Each extended, hard, filled No. 3 capsule USP containing a white powder, with the medium orange cap having the Parke-Davis logo printed in black ink and the white, opaque body having “DILANTIN” over “100 mg” printed in black ink, contains: phenytoin sodium 100 mg. Nonmedicinal ingredients: lactose, magnesium stearate, sugar and talc; capsule shell: D&C Red No. 28, FD&C Yellow No. 6, gelatin and titanium dioxide. Energy: 2.6 kJ (0.6 kcal). Sodium: <1 mmol (8.39 mg). Bottles of 100 and 1000.

Store at controlled room temperature 15-30°C. Protect from light and moisture.

Each extended, No. 4 Coni-Snap white capsule, manufacturer standard with pink cap, imprinted Parke-Davis and P-D 30 in black ink, contains: phenytoin sodium 30 mg. Nonmedicinal ingredients: lactose, magnesium stearate, sugar and talc; capsule shell: D&C Yellow No. 10, FD&C Red No. 3, gelatin and titanium dioxide. Energy: 3.0 kJ (0.7 kcal). Sodium: <1 mmol (2.52 mg). Bottles of 100.

A number of reports suggest an association between the use of anticonvulsant drugs by women with epilepsy and a higher incidence of birth defects in children born to these women. Data are more extensive with respect to phenytoin and phenobarbital, but these are also the most commonly prescribed anticonvulsant drugs; less systematic or anecdotal reports suggest a possible similar association with the use of all known anticonvulsant drugs.

The reports suggesting a higher incidence of birth defects in children of drug-treated epileptic women cannot be regarded as adequate to prove a definite cause and effect relationship. There are intrinsic methodologic problems in obtaining adequate data on drug teratogenicity in humans. Genetic factors or the epileptic condition itself may be more important than drug therapy in leading to birth defects. The great majority of mothers on anticonvulsant medication deliver normal infants. It is important to note that anticonvulsant drugs should not be discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus. The prescribing physician will wish to weigh these considerations in treating or counseling epileptic women of childbearing potential.

In addition to the reports of the increased incidence of congenital malformations, such as cleft lip/palate and heart malformations in children of women receiving phenytoin and other antiepileptic drugs, there have more recently been reports of a fetal hydantoin syndrome. This consists of prenatal growth deficiency, microcephaly and mental deficiency in children born to mothers who have received phenytoin, barbiturates, alcohol, or trimethadione. However, these features are all interrelated and are frequently associated with intrauterine growth retardation from other causes.

There have been isolated reports of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy.

An increase in seizure frequency during pregnancy occurs in a high proportion of patients, because of altered phenytoin absorption or metabolism. Periodic measurement of serum phenytoin levels is particularly valuable in the management of a pregnant epileptic patient as a guide to an appropriate adjustment of dosage. However, postpartum restoration of the original dosage will probably be indicated.

Neonatal coagulation defects have been reported within the first 24 hours in babies born to epileptic mothers receiving phenobarbital and/or phenytoin. Vitamin K has been shown to prevent or correct this defect and has been recommended to be given to the mother before delivery and to the neonate after birth.

Hemopoietic complications, some fatal, have occasionally been reported in association with administration of 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 (see Warnings).

nausea, vomiting, constipation, toxic hepatitis, and liver damage (see Precautions).

The most common manifestations encountered with Dilantin (extended phenytoin sodium capsules) therapy are referable to this system and are usually dose-related. These include nystagmus, ataxia, slurred speech, decreased coordination and mental confusion. Dizziness, insomnia, transient nervousness, motor twitchings, and headaches have also been observed. There have also been rare reports of 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 phenytoin therapy.

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, lupus erythematosus, and Stevens-Johnson syndrome and toxic epidermal necrolysis (see Precautions).

Hypersensitivity syndrome (which may include, but is not limited to symptoms such as arthralgias, eosinophilia, fever, liver dysfunction, lymphadenopathy or rash), systemic lupus erythematosus, periarteritis nodosa, and immunoglobulin abnormalities. Several individual case reports have suggested that there may be an increased, although still rare, incidence of hypersensitivity reactions, including skin rash and hepatotoxicity, in black patients.

coarsening of the facial features, enlargement of the lips, gingival hyperplasia, hypertrichosis and Peyronie's Disease.

The lethal dose of Dilantin (extended phenytoin sodium capsules) in pediatric patient 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, hyperflexia, 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 phenytoin plasma levels where toxicity may occur. Nystagmus on lateral gaze, usually appears at 80 µmol/L (20 µg/mL), ataxia at 119 µmol/L (30 µg/mL). Dysarthria and lethargy appear when serum concentration is >159 µmol/L (40 µg/mL), but a concentration as high as 198 µmol/L (50 µg/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 >396 µmol/L (100 µg/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 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 the presence of other CNS depressants, including alcohol, should be borne in mind.

Once-a-day dosage for adults with 300 mg of extended phenytoin sodium capsules may be considered if seizure control is established with divided doses of three 100 mg capsules daily. Studies comparing divided doses of 300 mg with a single daily dose of this quantity indicated that 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 only to be used for patients requiring this amount of drug daily. A major problem in motivating noncompliant patients may also be lessened when the patient can take all of his medication once-a-day. However, patients should be cautioned not to inadvertently miss a dose. Only extended phenytoin sodium capsules are recommended for once-a-day dosing.

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 may require the minimum adult dose (300 mg/day). Pediatric dosage forms available include a 30 mg extended phenytoin sodium capsule, a 50 mg palatably flavoured Infatab, or an oral suspension form containing 30 mg of phenytoin in each 5 mL.

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 40-80 µmol/L (10-20 µg/mL). Serum blood level determinations are especially helpful when possible drug interactions are suspected. With recommended dosage, a period of seven to ten days may be required to achieve therapeutic blood levels with Dilantin and changes in dosage (increase or decrease) should not be carried out at intervals shorter than 7 to 10 days.

Patients who have received no previous treatment may be started on one 100 mg extended phenytoin sodium capsule three times daily, and the dose then adjusted to suit individual requirements. For most adults, the satisfactory maintenance dosage will be three to four capsules (300-400 mg) daily. An increase to six capsules daily may be made, if necessary.