Dilantin 125

/ Pfizer

FOR ORAL ADMINISTRATION ONLY; NOT FOR PARENTERAL USE
Serum concentrations should be monitored and care should be taken when switching a patient from the sodium salt to the free acid form. The free acid form of phenytoin is used in Dilantin-125/5ml Suspension. 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 10–20 mcg/mL although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin. With recommended dosage, a period of seven to ten days may be required to achieve steady-state blood levels with phenytoin and changes in dosage (increase or decrease) should not be carried out at intervals shorter than seven to ten days.
Adult Dose: Patients who have received no previous treatment may be started on one teaspoonful (5 mL) of Dilantin-125/5ml Suspension three times daily, and the dose is then adjusted to suit individual requirements. An increase to five teaspoonfuls daily [625mg, (25ml)] may be made, if necessary.
An oral loading dose of phenytoin may be used for non-emergency initiation of therapy in adults who require rapid steady state serum levels, and for whom intravenous administration is not desirable. This dosing regimen should be reserved for patients in a clinic or hospital setting where phenytoin serum levels can be closely monitored. Patients with a history of renal or liver disease should not receive the oral loading dose regimen.
The recommended oral loading dose is one gram of phenytoin 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 phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution. Unbound phenytoin concentrations may be more useful in these patient populations.
Elderly Patients: 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 and adolescents may require the minimum adult dose (300 mg/day).

Dilantin (phenytoin) is indicated for the control of tonic-clonic (grand mal) and psychomotor (temporal lobe) seizures.

Dilantin is contraindicated in patients with:
• A history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins. Reactions have included angioedema.
• 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.

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 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: The drug can cause severe cutaneous adverse reactions (SCARs), which may be fatal. Reported reactions in phenytoin-treated patients have included toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome (SJS), acute generalized exanthematous pustulosis (AGEP), and Drug Reaction with Eosinophelia and Systemic Symptoms (DRESS). 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 a sever cutaneous adverse reaction, 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 SCARs.
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 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.
Angioedema: Angioedema has been reported in patients treated with DILANTIN in the post marketing setting. Treatment should be discontinued immediately if symptoms of angioedema, such as facial, perioral, or upper airway swelling occur. Treatment should be discontinued permanently if a clear alternative etiology for the reaction cannot be established.
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.

See prescribing information for full details.

• Withdrawal Precipitated Seizure, Status Epilepticus
• Suicidal Behavior and Ideation
• Serious Dermatologic Reactions
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity
• Hypersensitivity
• Cardiac Effects
• Angioedema
• Hepatic Injury
• Hematopoietic Complications
• Effects on Vitamin D and Bone
• Exacerbation of Porphyria
• Teratogenicity and Other Harm to the Newborn
• Hyperglycemia
See prescribing information for full details.

Phenytoin is extensively bound to plasma proteins and is prone to competitive displacement. 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 phenytoin concentrations and enhance the risk of drug toxicity. Monitoring of phenytoin serum levels is recommended when a drug interaction is suspected.
Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes.
See prescribing information for full details.

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 [see data]. There have been several reported cases of malignancies, including neuroblastoma, in children whose mothers received phenytoin during pregnancy.
Administration of phenytoin to pregnant animals resulted in an increased incidence of fetal malformations and other manifestations of developmental toxicity (including embryofetal death, growth impairment, and behavioral abnormalities) in multiple species at clinically relevant doses.
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.

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.