DILANTIN® (extended phenytoin sodium capsules)

DILANTIN® (extended phenytoin sodium capsules)

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DILANTIN® (extended phenytoin sodium capsules)

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

Indications and usage

DILANTIN is indicated for the treatment of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures and prevention and treatment of seizures occurring during or following neurosurgery

Mechanism of Action

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

Dosage and administration

Divided daily dosage: The recommended starting dose for adult patients who have received no previous treatment is one 100-mg DILANTIN (extended phenytoin sodium capsule, USP) by mouth three times daily. Adjust the dosage to suit individual requirements up to a maximum of two capsules three times a day. For most adults, the satisfactory maintenance dosage will be one capsule three to four times a day.

Once-a-day dosage: In adults, if seizure control is established with divided doses of three 100-mg DILANTIN (extended phenytoin sodium capsules, USP) daily, once-a-day dosage with 300 mg of DILANTIN (extended phenytoin sodium capsules, USP) may be considered.

Pediatric Dosage: The recommended starting dosage for pediatric patients is 5 mg/kg/day by mouth in two or three equally divided doses, with subsequent dosage individualized to a maximum of 300 mg daily in divided doses. A recommended daily maintenance dosage is usually 4 to 8 mg/kg/day in equally divided doses. Children over 6 years and adolescents may require the minimum adult dosage (300 mg/day).

Contraindications

DILANTIN is contraindicated in patients with:

  • A history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins.
  • A history of prior acute hepatotoxicity attributable to phenytoin.
  • Coadministration with delavirdine because of the potential for loss of virologic response and possible resistance to delavirdine or to the class of non-nucleoside reverse transcriptase inhibitors.

Warnings and precautions

Withdrawal Precipitated Seizure, Status Epilepticus: Abrupt withdrawal of 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 anticonvulsant medication arises, this should be done gradually. However, 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 anticonvulsant drug not belonging to the hydantoin chemical class.

Suicidal Behavior and Ideation: Antiepileptic drugs (AEDs), including DILANTIN, 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.

Serious Dermatologic Reactions: Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and StevensJohnson syndrome (SJS), have been reported with phenytoin treatment. The onset of symptoms is usually within 28 days, but can occur later. DILANTIN 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 (DRESS)

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 DILANTIN. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, 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. DILANTIN should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

Hypersensitivity: DILANTIN and other hydantoins are contraindicated in patients who have experienced 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 DILANTIN.

Cardiac Effects: Cases of bradycardia and cardiac arrest have been reported in DILANTIN-treated patients, both at recommended phenytoin doses and levels, and in association with phenytoin toxicity. Most of the reports of cardiac arrest occurred in patients with underlying cardiac disease.

Hepatic Injury: Cases of acute hepatotoxicity, including infrequent cases of acute hepatic failure, have been reported with DILANTIN. 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 phenytoin hepatotoxicity ranges from prompt recovery to fatal outcomes. In these patients with acute hepatotoxicity, DILANTIN should be immediately discontinued and not readministered.

Hematopoietic Complications: Hematopoietic complications, some fatal, have occasionally been reported in association with administration of DILANTIN. These have included thrombocytopenia, leukopenia, granulocytopenia, agranulocytosis, and pancytopenia with or without bone marrow suppression.

Effects on Vitamin D and Bone: The chronic use of phenytoin in patients with epilepsy has been associated with decreased bone mineral density (osteopenia, osteoporosis, and osteomalacia) and bone fractures. 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.

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Renal or Hepatic Impairment or Hypoalbuminemia: Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients.

Exacerbation of Porphyria: In view of isolated reports associating phenytoin with exacerbation of porphyria, caution should be exercised in using this medication in patients suffering from this disease.

Teratogenicity and Other Harm to the Newborn: DILANTIN may cause fetal harm when administered to a pregnant woman. Prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes

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

Hyperglycemia: 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.

Serum Phenytoin Levels above Therapeutic Range: Serum levels of phenytoin sustained above the therapeutic range may produce confusional states referred to as “delirium,” “psychosis,” or “encephalopathy,” or rarely irreversible cerebellar dysfunction and/or cerebellar atrophy. Accordingly, at the first sign of acute toxicity, serum levels should be immediately checked. Dose reduction of phenytoin therapy is indicated if serum levels are excessive; if symptoms persist, termination is recommended.

Drug interactions

Drugs that may increase phenytoin serum levels:

Antiepileptic drugs: Ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate

Azoles: Fluconazole, ketoconazole, itraconazole, miconazole, voriconazole

Antineoplastic agents: Capecitabine, fluorouracil

Antidepressants: Fluoxetine, fluvoxamine, sertraline

Gastric acid reducing agents: H2 antagonists (cimetidine), omeprazole

Sulfonamides: Sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazoletrimethoprim

Drugs that may decrease phenytoin serum levels

Antacids: Calcium carbonate, aluminum hydroxide, magnesium hydroxide

Antineoplastic agents usually in combination: Bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate

Antiviral agents: Fosamprenavir, nelfinavir, ritonavir

Antiepileptic drugs: Carbamazepine, vigabatrin

Use in specific populations

Pregnancy: In humans, prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse developmental outcomes. Prenatal phenytoin exposure is associated with an increased incidence of major malformations, including orofacial clefts and cardiac defects. In addition, the fetal hydantoin syndrome, a pattern of abnormalities including dysmorphic skull and facial features, nail and digit hypoplasia, growth abnormalities (including microcephaly), and cognitive deficits has been reported among children born to epileptic women who took phenytoin alone or in combination with other antiepileptic drugs during pregnancy. There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers’ received phenytoin during pregnancy.

Lactation: Phenytoin is secreted in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DILANTIN and any potential adverse effects on the breastfed infant from DILANTIN or from the underlying maternal condition.

Pediatric Use: 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 dosage (300 mg/day)

Geriatric Use: Phenytoin clearance tends to decrease with increasing age. Lower or less frequent dosing may be required

Renal and/or Hepatic Impairment or Hypoalbuminemia: The liver is the chief site of biotransformation of phenytoin; patients with impaired liver function, elderly patients, or those who are gravely ill may show early signs of toxicity.

Because the fraction of unbound phenytoin is increased in patients with renal or hepatic disease, or in those with hypoalbuminemia, the monitoring of phenytoin serum levels should be based on the unbound fraction in those patients.

Overdosage

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, blurred vision, nausea, and vomiting. The patient may become comatose and hypotensive. Bradycardia and cardiac arrest have been reported. Death is caused by respiratory and circulatory depression.

There are marked variations among individuals with respect to phenytoin serum 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 serum 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. Irreversible cerebellar dysfunction and atrophy have been reported.

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 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.

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