Drug: Dilantin

Dilantin (phenytoin sodium injection, USP) is a ready-mixed solution of phenytoin sodium in a vehicle containing 40% propylene glycol and 10% alcohol in water for injection, adjusted to pH 12 with sodium hydroxide. Phenytoin sodium 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 represented by the following structural formula:

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The most notable signs of toxicity associated with the intravenous use of this drug are cardiovascular collapse and/or central nervous system depression. Hypotension does occur when the drug is administered rapidly by the intravenous route. The rate of administration is very important; it should not exceed 50 mg per minute in adults, and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Body As a Whole: Allergic reactions in the form of rash and rarely more serious forms (see Skin and Appendages paragraph below) and DRESS (see WARNINGS) 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. Cardiovascular: Severe cardiovascular events and fatalities have been reported with atrial and ventricular conduction depression and ventricular fibrillation. Severe complications are most commonly encountered in elderly or critically ill patients (see WARNINGS). Nervous System: The most common manifestations encountered with phenytoin therapy are referable to this system and are usually dose-related. These include nystagmus, ataxia, slurred speech, decreased coordination, somnolence, and mental confusion. Dizziness, insomnia, transient nervousness, motor twitchings, paresthesia, 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. Digestive System: Nausea, vomiting, constipation, enlargement of the lips, 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 (see WARNINGS section). There have also been reports of hypertrichosis. Local irritation, inflammation, tenderness, necrosis, and sloughing have been reported with or without extravasation of intravenous phenytoin (see WARNINGS). Hematologic and Lymphatic System: Hematopoietic 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). Special Senses: Altered taste sensation including metallic taste. Urogenital: Peyronie's disease Read the Dilantin (phenytoin) Side Effects Center for a complete guide to possible side effectsLearn More »

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Because of the increased risk of adverse cardiovascular reactions associated with rapid administration, intravenous administration should not exceed 50 mg per minute in adults. In pediatric patients, the drug should be administered at a rate not exceeding 1-3 mg/kg/min or 50 mg per minute, whichever is slower. As non-emergency therapy, Dilantin should be administered more slowly as either a loading dose or by intermittent infusion. Because of the risks of cardiac and local toxicity associated with intravenous Dilantin, oral phenytoin should be used whenever possible. Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac monitoring is needed during and after the administration of intravenous Dilantin. Reduction in rate of administration or discontinuation of dosing may be needed. Because of the risk of local toxicity, intravenous Dilantin should be administered directly into a large peripheral or central vein through a large-gauge catheter. Prior to the administration, the patency of the IV catheter should be tested with a flush of sterile saline. Each injection of parenteral Dilantin should then be followed by a flush of sterile saline through the same catheter to avoid local venous irritation due to the alkalinity of the solution. Dilantin can be given diluted with normal saline. The addition of parenteral Dilantin to dextrose and dextrose-containing solutions should be avoided due to lack of solubility and resultant precipitation. Treatment with Dilantin can be initiated either with a loading dose or an infusion: Loading Dose: A loading dose of parenteral Dilantin should be injected slowly, not exceeding 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Infusion: For infusion administration, parenteral Dilantin should be diluted in normal saline with the final concentration of Dilantin in the solution no less than 5 mg/mL. Administration should commence immediately after the mixture has been prepared and must be completed within 1 to 4 hours (the infusion mixture should not be refrigerated). An in-line filter (0.22-0.55 microns) should be used. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution or container permit. The diluted infusion mixture (Dilantin plus normal saline) should not be refrigerated. If the undiluted parenteral Dilantin is refrigerated or frozen, a precipitate might form: this will dissolve again after the solution is allowed to stand at room temperature. The product is still suitable for use. A faint yellow coloration may develop, however this has no effect on the potency of the solution. Status Epilepticus In adults, a loading dose of 10 to 15 mg/kg should be administered slowly intravenously, at a rate not exceeding 50 mg per minute (this will require approximately 20 minutes in a 70-kg patient). The loading dose should be followed by maintenance doses of 100 mg orally or intravenously every 6-8 hours. In the pediatric population, a loading dose of 15-20 mg/kg of Dilantin intravenously will usually produce plasma concentrations of phenytoin within the generally accepted therapeutic range (10-20 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 1-3 mg/kg/min or 50 mg per minute, whichever is slower. Continuous monitoring of the electrocardiogram and blood pressure is essential. The patient should be observed for signs of respiratory depression. Determination of phenytoin plasma levels is advised when using Dilantin in the management of status epilepticus and in the subsequent establishment of maintenance dosage. Other measures, including concomitant administration of an intravenous benzodiazepine such as diazepam, or an intravenous short-acting barbiturate, will usually be necessary for rapid control of seizures because of the required slow rate of administration of Dilantin. If administration of Parenteral Dilantin does not terminate seizures, the use of other anticonvulsants, intravenous barbiturates, general anesthesia, and other appropriate measures should be considered. Intramuscular administration should not be used in the treatment of status epilepticus because the attainment of peak plasma levels may require up to 24 hours. Nonemergent Loading And Maintenance Dosing Because of the risks of cardiac and local toxicity associated with intravenous Dilantin, oral phenytoin should be used whenever possible. In adults, a loading dose of 10 to 15 mg/kg should be administered slowly. The rate of intravenous administration should not exceed 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Slower administration rates are recommended to minimize the cardiovascular adverse reactions. Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential. The loading dose should be followed by maintenance doses of oral or intravenous Dilantin every 6-8 hours. Ordinarily, Dilantin should not be given intramuscularly because of the risk of necrosis, abscess formation, and erratic absorption. If intramuscular administration is required, compensating dosage adjustments are necessary to maintain therapeutic plasma levels. An intramuscular dose 50% greater than the oral dose is necessary to maintain these levels. When returned to oral administration, the dose should be reduced by 50% of the original oral dose for one week to prevent excessive plasma levels due to sustained release from intramuscular tissue sites. Monitoring plasma levels would help prevent a fall into the subtherapeutic range. Serum blood level determinations are especially helpful when possible drug interactions are suspected. IV Substitution For Oral Phenytoin Therapy When treatment with oral phenytoin is not possible, IV Dilantin can be substituted for oral phenytoin at the same total daily dose. Dilantin capsules are approximately 90% bioavailable by the oral route. Phenytoin is 100% bioavailable by the IV route. For this reason, plasma phenytoin concentrations may increase modestly when IV phenytoin is substituted for oral phenytoin sodium therapy. The rate of administration for IV Dilantin should be no greater than 50 mg per minute in adults and 1-3 mg/kg/min (or 50 mg per minute, whichever is slower) in pediatric patients. Serum concentrations should be monitored and care should be taken when switching a patient from the sodium salt to the free acid form. Dilantin® Kapseals® and Dilantin Parenteral are formulated with the sodium salt of phenytoin. The free acid form of phenytoin is used in Dilantin-125 Suspension and Dilantin Infatabs. 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. 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 A loading dose of 15-20 mg/kg of Dilantin intravenously will usually produce plasma concentrations of phenytoin within the generally accepted therapeutic range (1020 mcg/mL). The drug should be injected slowly intravenously at a rate not exceeding 13 mg/kg/min or 50 mg per minute, whichever is slower.

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Phenytoin is extensively bound to serum 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. Phenytoin is a potent inducer of hepatic drug-metabolizing enzymes. Serum level determinations for 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 phenytoin concentrations:
  • Drugs that may increase phenytoin serum levels, include: acute alcohol intake, amiodarone, anti-epileptic agents (ethosuximide, felbamate, oxcarbazepine, methsuximide, topiramate), azoles (fluconazole, ketoconazole, itraconazole, voriconazole), capecitabine, chloramphenicol, chlordiazepoxide, cimetidine, diazepam, disulfiram, estrogens, fluorouracil, fluoxetine, fluvastatin, fluvoxamine, H2-antagonists (e.g. cimetidine), halothane, isoniazid, methylphenidate, omeprazole, phenothiazines, salicylates, sertraline, succinimides, sulfonamides (e.g., sulfamethizole, sulfaphenazole, sulfadiazine, sulfamethoxazole-trimethoprim), ticlopidine, tolbutamide, trazodone, and warfarin.
  • Drugs that may decrease phenytoin levels, include: anticancer drugs usually in combination (e.g., bleomycin, carboplatin, cisplatin, doxorubicin, methotrexate), carbamazepine, chronic alcohol abuse, folic acid, fosamprenavir, nelfinavir, reserpine, ritonavir, St. John's Wort, and vigabatrin.
  • Drugs that may either increase or decrease phenytoin serum levels include: phenobarbital, sodium valproate, and valproic acid. Similarly, the effect of phenytoin on phenobarbital, valproic acid and sodium valproate serum levels is unpredictable.
  • The addition or withdrawal of the agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome.
Drugs affected by phenytoin:
  • Drugs that should not be coadministered with phenytoin: Delavirdine (see CONTRAINDICATIONS).
  • Drugs whose efficacy is impaired by phenytoin include: azoles (fluconazole, ketoconazole, itraconazole, voriconazole, posaconazole), corticosteroids, doxycycline, estrogens, furosemide, irinotecan, oral contaceptives, paclitaxel, paroxetine, quinidine, rifampin, sertraline, tenisposide, theophylline, and Vitamin D.
  • Increased and decreased PT/INR responses have been reported when phenytoin is coadministered with warfarin.
  • Phenytoin decreases plasma concentrations of certain HIV antivirals ( efavirenz, lopinavir/ritonavir, indinavir, nelfinavir, ritonavir, saquinavir), anti-epileptic agents (felbamate, topiramate, oxcarbazepine, quetiapine), atorvastatin, cyclosporine, digoxin, fluvastatin, folic acid, mexiletine, nisoldipine, praziquantel, and simvastatin.
  • Phenytoin when given with fosamprenavir alone may decrease the concentration of amprenavir, the active metabolite. Phenytoin when given with the combination of fosamprenavir and ritonavir may increase the concentration of amprenavir.
  • Resistance to the neuromuscular blocking action of the nondepolarizing neuromuscular blocking agents pancuronium, vecuronium, rocuronium, and cisatracurium has occurred in patients chronically administered phenytoin. Whether or not phenytoin has the same effect on other non-depolarizing agents is unknown. Patients should be monitored closely for more rapid recovery from neuromuscular blockade than expected, and infusion rate requirements may be higher.
  • The addition or withdrawal of phenytoin during concomitant therapy with these agents may require adjustment of the dose of these agents to achieve optimal clinical outcome.
Drug-Enteral Feeding/Nutritional Preparations Interaction Literature reports suggest that patients who have received enteral feeding preparations and/or related nutritional supplements have lower than expected 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. Drug/Laboratory Test Interactions Phenytoin may decrease serum concentrations of T4. It may also produce lower than normal values for dexamethasone or metyrapone tests. Phenytoin may also cause increased serum levels of glucose, alkaline phosphatase, and gamma glutamyl transpeptidase (GGT). Care should be taken when using immunoanalytical methods to measure plasma phenytoin concentrations following fosphenytoin administration. Last reviewed on RxList: 2/7/2014
This monograph has been modified to include the generic and brand name in many instances.

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Parenteral Dilantin is indicated for the control of generalized tonic-clonic status epilepticus, and prevention and treatment of seizures occurring during neurosurgery. Parenteral Dilantin should be used only when oral Dilantin administration is not possible.

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Phenytoin is contraindicated in patients with a history of hypersensitivity to phenytoin, its inactive ingredients, or other hydantoins. Because of its effect on ventricular automaticity, phenytoin is contraindicated in sinus bradycardia, sino-atrial block, second and third degree A-V block, and patients with Adams-Stokes syndrome. Coadministration of Dilantin is contraindicated with delavirdine due to potential for loss of virologic response and possible resistance to delavirdine or to the class of nonnucleoside reverse transcriptase inhibitors. Last reviewed on RxList: 2/7/2014
This monograph has been modified to include the generic and brand name in many instances.

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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 phenytoin plasma levels where toxicity may occur. Nystagmus, on lateral gaze, usually appears at 20 mcg/mL, ataxia at 30 mcg/mL, dysarthria and lethargy appear when the plasma concentration is over 40 mcg/mL, but as high a concentration as 50 mcg/mL has been reported without evidence of toxicity. As much as 25 times the therapeutic dose has been taken to result in a serum concentration over 100 mcg/mL with complete recovery. Treatment: Treatment is nonspecific since there is no known antidote. The adequacy of the respiratory and circulatory systems should be carefully observed and appropriate supportive measures employed. Hemodialysis can be considered since 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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NDC 0071-4488--47 (Steri-Dose® 4488) Dilantin ready-mixed solution containing 50 mg phenytoin sodium per milliliter is supplied in a 2-mL sterile disposable syringe(22 gauge x 1 ¼ inch needle). Packages of ten syringes. NDC 0071-4488-45 Dilantin ready-mixed solution containing 50 mg phenytoin sodium per milliliter is supplied in 2-mL Steri-Vials®. Packages of twenty-five. NDC 0071-4475-45 Dilantin ready-mixed solution containing 50 mg phenytoin sodium per milliliter is supplied in 5-mL Steri-Vials. Packages of twenty-five. Caution Federal law prohibits dispensing without prescription. Warning-Manufactured with CFC-12, which harms public health and environment by destroying ozone in the upper atmosphere. Distributed by: Parke-Davis, Division of Pfizer Inc, NY, NY 10017. January 2014 Last reviewed on RxList: 2/7/2014
This monograph has been modified to include the generic and brand name in many instances.

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General The liver is the site of biotransformation. Patients with impaired liver function, elderly patients, or those who are gravely ill may show early 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. Hyperglycemia, resulting from the drug's inhibitory effect on insulin release, has been reported. Phenytoin may also raise the serum glucose level in diabetic patients. 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 seizures. If tonic-clonicand absence 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 levels are recommended. Dose reduction of phenytoin therapy is indicated if plasma levels are excessive; if symptoms persist, termination is recommended. (See WARNINGS) Laboratory Tests Phenytoin serum level determinations may be necessary to achieve optimal dosage adjustments. Phenytoin doses are usually selected to attain therapeutic plasma total phenytoin concentrations of 10 to 20 mcg/mL (unbound phenytoin concentrations of 1 to 2 mcg/mL). Carcinogenesis See “WARNINGS” section for information on carcinogenesis. Pregnancy Pregnancy Category D: See WARNINGS. Nursing Mothers Infant breast feeding is not recommended for women taking this drug because phenytoin appears to be secreted in low concentrations in human milk. Pediatric Use See DOSAGE AND ADMINISTRATION Geriatric Use Phenytoin clearance tends to decrease with increasing age (see CLINICAL PHARMACOLOGY: Special Populations). Last reviewed on RxList: 2/7/2014
This monograph has been modified to include the generic and brand name in many instances.

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