The addition or withdrawal of these agents in patients on phenytoin therapy may require an adjustment of the phenytoin dose to achieve optimal clinical outcome.

Drugs Affected by Phenytoin Table 2 includes commonly occurring drugs interactions affected by phenytoin. Individual drug package inserts should be consulted. 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.

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. This can be done by calling the toll free number , and must be done by patients themselves. Risk Summary In humans, prenatal exposure to phenytoin may increase the risks for congenital malformations and other adverse development outcomes. An increased incidence of major malformations such as orofacial clefts and cardiac defects and abnormalities characteristic of fetal hydantoin syndrome 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. Clinical Considerations Disease-associated maternal risk An increase in seizure frequency may occur during pregnancy because of altered phenytoin pharmacokinetics.

However, postpartum restoration of the original dosage will probably be indicated. Data Animal data Administration of phenytoin to pregnant rats, rabbits, and mice during organogenesis resulted in embryofetal death, fetal malformations, and decreased fetal growth retardation.

Malformations including craniofacial, cardiovascular, neural, limb, and digit abnormalities were observed in rats, rabbits, and mice at doses as low as , 75, and Lactation Risk Summary Phenytoin is secreted in human milk. Patients with impaired liver function, elderly patients, or those who are gravely ill may show early 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. Death is caused by respiratory and circulatory depression. There are marked variations among individuals with respect to phenytoin serum levels where toxicity may occur.

Irreversible cerebellar dysfunction and atrophy have been reported. 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. 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: Phenytoin Sodium - Clinical Pharmacology 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.

Pharmacokinetics Absorption A fall in serum levels may occur when patients are changed from oral to intramuscular administration. The drop is caused by slower absorption, as compared to oral administration, because of the poor water solubility of phenytoin. Intravenous administration is the preferred route for producing rapid therapeutic serum levels. Patients stabilized on a daily oral regimen of phenytoin experience a drop in peak blood levels to percent of stable levels if crossed over to an equal dose administered intramuscularly.

However, the intramuscular depot of poorly soluble material is eventually absorbed, as determined by urinary excretion of 5 p-hydroxyphenyl phenylhydantoin HPPH , the principal metabolite, as well as the total amount of drug eventually appearing in the blood. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal.

A short-term one week study indicates that patients do not experience the expected drop in blood levels when crossed over to the intramuscular route if the phenytoin IM dose is increased by 50 percent over the previously established oral dose. To avoid drug accumulation caused by absorption from the muscle depots, it is recommended that for the first week back on oral phenytoin, the dose be reduced to half of the original oral dose one-third of the IM dose.

Experience for periods greater than one week is lacking and blood level monitoring is recommended. Distribution Phenytoin is extensively bound to plasma proteins and is prone to competitive displacement. Elimination The serum half-life in man after intravenous administration ranges from 10 to 15 hours. Excretion Most of the drug is excreted in the bile as inactive metabolites. However, cardiac events have also been reported in adults and children without underlying cardiac disease or comorbidities and at recommended doses and infusion rates.

Intravenous administration should not exceed 50 mg per minute in adults. Although the risk of cardiovascular toxicity increases with infusion rates above the recommended infusion rate, these events have also been reported at or below the recommended infusion rate. Because adverse cardiovascular reactions have occurred during and after infusions, careful cardiac and respiratory monitoring is needed during and after the administration of intravenous DILANTIN.

Reduction in rate of administration or discontinuation of dosing may be needed. Withdrawal Precipitated Seizure, Status Epilepticus Antiepileptic drugs should not be abruptly discontinued because of the possibility of increased seizure frequency, including 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.

However, in the event of an allergic or hypersensitivity reaction, 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. Serious Dermatologic Reactions Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis TEN and Stevens-Johnson syndrome SJS , have been reported with phenytoin treatment. The onset of symptoms is usually within 28 days, but can occur later.

Some of these events have been fatal or life-threatening. 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. Additionally, consider alternatives to structurally similar drugs such as carboxamides e. 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.

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.

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 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.

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. Local Toxicity Including Purple Glove Syndrome Soft tissue irritation and inflammation has occurred at the site of injection with and without extravasation of intravenous phenytoin.

Soft tissue irritation may vary from slight tenderness to extensive necrosis , and sloughing. The syndrome may not develop for several days after injection. In the absence of severe adverse reactions, increase gefitinib dose to mg daily in patients receiving strong CYP3A4 inducers; resume mg dose 7 days after discontinuation of the strong inducer. Carefully monitor clinical response. Consider therapy modification Gemigliptin: Fosphenytoin-Phenytoin may decrease the serum concentration of Gestrinone.

Monitor therapy Glecaprevir and Pibrentasvir: Increase the guanfacine dose by up to double when initiating concomitant therapy with strong CYP3A4 inducers. Increase guanfacine dose gradually over weeks if strong CYP3A4 inducer therapy is just beginning.

Consider therapy modification Halothane: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification Hydrocortisone Systemic: Avoid concurrent use of imatinib with strong CYP3A4 inducers when possible.

Consider therapy modification Irinotecan Products: Specifically, serum concentrations of SN may be reduced. Avoid combination Isavuconazonium Sulfate: Consider therapy modification Itraconazole: Avoid this combination whenever possible. Consider therapy modification Ixazomib: Avoid combination Kava Kava: Phenytoin may decrease the serum concentration of Lacosamide. Phenytoin may decrease the serum concentration of LamoTRIgine. Consider therapy modification Lapatinib: Monitor therapy Leucovorin Calcium-Levoleucovorin: Phenytoin may diminish the therapeutic effect of Levodopa.

Strongly consider using an alternative to any strong CYP3A4 inducer in patients who are being treated with linagliptin. If this combination is used, monitor patients closely for evidence of reduced linagliptin effectiveness. Consider therapy modification Linagliptin: Strongly consider using an alternative to any strong P-glycoprotein inducer in patients who are being treated with linagliptin.

Consider therapy modification Lithium: Monitor therapy Loop Diuretics: Phenytoin may diminish the diuretic effect of Loop Diuretics. Phenytoin may decrease the serum concentration of Lopinavir. Lopinavir may decrease the serum concentration of Phenytoin. Consider therapy modification Lumacaftor: Avoid combination Magnesium Sulfate: Consider avoiding concomitant use of manidipine and strong CYP3A4 inducers. If combined, monitor closely for decreased manidipine effects and loss of efficacy.

Increased manidipine doses may be required. Consider therapy modification Maraviroc: Increase maraviroc adult dose to mg twice daily when used with strong CYP3A4 inducers. This does not apply to patients also receiving strong CYP3A4 inhibitors. Consider therapy modification Mebendazole: Phenytoin may decrease the serum concentration of Mebendazole. May diminish the therapeutic effect of Anticonvulsants. Mefloquine may decrease the serum concentration of Anticonvulsants.

Mefloquine is contraindicated for malaria prophylaxis in persons with a history of convulsions. Monitor anticonvulsant concentrations and treatment response closely with concurrent use. Consider therapy modification Meperidine: Phenytoin may decrease the serum concentration of Meperidine.

Phenytoin may decrease the serum concentration of Methadone. Fosphenytoin-Phenytoin may increase the serum concentration of Methotrexate. Specifically, fosphenytoin-phenytoin may displace methotrexate from serum proteins, increasing the concentration of free, unbound drug. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification Methylfolate: Consider methylprednisolone dose increases in patients receiving strong CYP3A4 inducers and monitor closely for reduced steroid efficacy.

The oral metyrapone test would thus be unreliable unless the metapyrone dosage was substantially increased e. Phenytoin may decrease the serum concentration of Mexiletine. Phenytoin may decrease the serum concentration of Mianserin. Monitor therapy Miconazole Oral: Consider avoiding the concomitant use of mirodenafil and strong CYP3A4 inducers. If combined, monitor for decreased mirodenafil effects.

Mirodenafil dose increases may be required to achieve desired effects. Phenytoin may decrease the serum concentration of Nelfinavir. Avoid combination Neuromuscular-Blocking Agents Nondepolarizing: Fosphenytoin-Phenytoin may diminish the neuromuscular-blocking effect of Neuromuscular-Blocking Agents Nondepolarizing.

Fosphenytoin-Phenytoin may enhance the neuromuscular-blocking effect of Neuromuscular-Blocking Agents Nondepolarizing. Fosphenytoin-Phenytoin may decrease the serum concentration of Neuromuscular-Blocking Agents Nondepolarizing. Phenytoin may decrease the serum concentration of NIFEdipine. Avoid combination Nitric Oxide: Combinations of these agents may increase the likelihood of significant methemoglobinemia. Monitor patients for signs of methemoglobinemia e.

Phenytoin may decrease the serum concentration of Omeprazole. Omeprazole may increase the serum concentration of Phenytoin. Monitor therapy Opioid Analgesics: Avoid concomitant use of opioid analgesics and benzodiazepines or other CNS depressants when possible. Consider therapy modification Orlistat: May decrease the serum concentration of Anticonvulsants. Consider therapy modification OXcarbazepine: Fosphenytoin-Phenytoin may decrease serum concentrations of the active metabolite s of OXcarbazepine.

Specifically, concentrations of the major active monohydroxy metabolite may be reduced. OXcarbazepine may increase the serum concentration of Fosphenytoin-Phenytoin. No specific recommendations are available for other oxcarbazepine formulations. Consider therapy modification Oxomemazine: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. Consider therapy modification Palbociclib: Avoid using the 3-month extended-release injectable suspension Invega Trinza with inducers of both CYP3A4 and P-glycoprotein during the 3-month dosing interval if possible.

If combination is necessary, consider using extended-release tablets. Consider therapy modification Panobinostat: Phenytoin may decrease the serum concentration of Perampanel. PHENobarbital may decrease the serum concentration of Phenytoin.

Phenytoin may increase the serum concentration of PHENobarbital. Monitor therapy Platinum Derivatives: CNS Depressants may enhance the sedative effect of Pramipexole. Avoid concomitant use of praziquantel with strong CYP3A4 inducers. Discontinue rifampin 4 weeks prior to initiation of praziquantel therapy. Rifampin may be resumed the day following praziquantel completion. Phenytoin may increase the metabolism of Primidone.

The ratio of primidone: Monitor therapy Progestins Contraceptive: Phenytoin may diminish the therapeutic effect of Progestins Contraceptive. Use of an alternative, nonhormonal contraceptive is recommended. Consider therapy modification Propacetamol: Fosphenytoin-Phenytoin may decrease serum concentrations of the active metabolite s of Propacetamol.

Specifically, serum concentrations of acetaminophen may be decreased leading to decreased efficacy , but the formation of its toxic N-acetyl-p-benzoquinone imine NAPQI metabolite may be increased leading to increased hepatotoxicity. May increase the metabolism of Phenytoin. This is most apparent in high pyridoxine doses e. An increase in quetiapine dose as much as 5 times the regular dose may be required to maintain therapeutic benefit. Consider therapy modification QuiNIDine: Phenytoin may decrease the serum concentration of QuiNIDine.

Consider therapy modification Radotinib: Consider alternatives to this combination when possible as the risk of radotinib treatment failure may be increased. Consider therapy modification Ramelteon: Seek alternatives when possible. Consider therapy modification Rifapentine: Phenytoin may decrease the serum concentration of Rilpivirine.

Consider increasing the dose of oral risperidone to no more than double the original dose if a strong CYP3A4 inducer is initiated. For patients on IM risperidone, consider an increased IM dose or supplemental doses of oral risperidone. Consider therapy modification Ritonavir: Phenytoin may decrease the serum concentration of Ritonavir. Ritonavir may decrease the serum concentration of Phenytoin. Consider therapy modification Rivaroxaban: The Canadian product monograph makes no such recommendation but notes that such agents may reduce roflumilast therapeutic effects.

Avoid rolapitant use in patients requiring chronic administration of strong CYP3A4 inducers. Monitor for reduced rolapitant response and the need for alternative or additional antiemetic therapy even with shorter-term use of such inducers.

Consider therapy modification RomiDEPsin: CNS Depressants may enhance the sedative effect of Rotigotine. Phenytoin may decrease the serum concentration of Rufinamide. Monitor therapy Selective Serotonin Reuptake Inhibitors: Specifically, the risk of psychomotor impairment may be enhanced. Phenytoin may decrease the serum concentration of Sertraline.

Avoid concomitant use of strong CYP3A4 inducers and sirolimus if possible. If combined, monitor for reduced serum sirolimus concentrations. Sirolimus dose increases will likely be necessary to prevent subtherapeutic sirolimus levels. Consider therapy modification Sodium Nitrite: Monitor therapy Sodium Oxybate: Consider alternatives to combined use.

Variations within the CYP2C9 gene that result in decreased enzymatic activity have been associated with increased phenytoin concentrations, as well as reports of drug toxicities due to these increased concentrations. Phenytoin induces metabolizing enzymes in the liver. This leads to increased metabolism of vitamin D , thus decreased vitamin D levels.

Vitamin D deficiency , as well as low calcium and phosphate in the blood cause decreased bone mineral density. Antacids administered in a peptic ulcer regimen may decrease the AUC of a single dose of phenytoin. Patients should be cautioned against concomitant use of antacids and phenytoin. Consider using other options if possible.

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