Drug Interactions between fosphenytoin and modafinil

Information for this minor interaction is available on the professional version.

Hematologic toxicities have been associated with the use of hydantoin anticonvulsants, particularly mephenytoin. Thrombocytopenia, leukopenia, neutropenia, agranulocytosis, pancytopenia and, rarely, hemolytic anemia, aplastic anemia and pure red cell aplasia have been reported. Therapy with hydantoin anticonvulsants should be administered cautiously in patients with preexisting blood dyscrasias and/or bone marrow depression. Complete blood counts, including platelets, should be performed prior to initiating therapy and regularly for several months thereafter. For mephenytoin, the manufacturer recommends performing counts after 2 weeks on a low dosage, after another 2 weeks when full dosage is reached, then monthly for a year, and every 3 months thereafter. Marked depression of blood counts may be indication for withdrawal of hydantoin therapy.

The use of CNS stimulants can cause psychotic symptoms, suicidal ideation, and aggression, and can exacerbate symptoms of behavior disturbance and thought disorder; CNS stimulants may induce a manic or mixed episode in patients with bipolar disorder. Psychiatric symptoms have been reported in patients with and without history of psychiatric disorders. All patients (particularly those with psychotic or bipolar disorders) should be monitored closely, especially during treatment initiation and at times of dose changes. Extreme caution should be exercised when CNS stimulants are given to patients with a history of psychosis, depression, mania, or bipolar disorder. Prior to initiating therapy, all patients should be screened for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or family history of suicide, bipolar disease, or depression). If any psychiatric symptoms emerge or are exacerbated, treatment suspension should be considered. Some CNS stimulants are contraindicated in patients with marked agitation or anxiety.

The intravenous administration of phenytoin or its prodrug, fosphenytoin, is contraindicated in patients with sinus bradycardia, sino-atrial block, second and third degree AV block, and patients with Adam-Stokes syndrome. Severe cardiotoxic reactions related to depression of atrial and ventricular conduction and ventricular fibrillation have been reported with parenteral phenytoin, primarily in elderly or gravely ill patients. Hypotension and cardiovascular collapse have also been reported, usually when the drug was administered too rapidly. Therapy with intravenous phenytoin or fosphenytoin should be administered cautiously in patients with hypotension or severe myocardial insufficiency, particularly if they are elderly or seriously ill. The rate of injection should not exceed manufacturer recommendations and should be adjusted based on the patient's cardiovascular status. The rate of IV administration for SESQUIENT should not exceed 0.4 mg PE/kg/min in pediatric patients as safety at a faster rate has not been established.

CNS stimulants increase blood pressure and heart rate; the use of some agents may be contraindicated in patients with severe/uncontrolled hypertension. Caution should be used when administering to patients with preexisting high blood pressure (even mild hypertension) and other cardiovascular conditions. All patients under treatment should be regularly monitored for potential tachycardia and hypertension.

The intravenous administration of phenytoin or its prodrug, fosphenytoin, is contraindicated in patients with sinus bradycardia, sino-atrial block, second and third degree AV block, and patients with Adam-Stokes syndrome. Severe cardiotoxic reactions related to depression of atrial and ventricular conduction and ventricular fibrillation have been reported with parenteral phenytoin, primarily in elderly or gravely ill patients. Hypotension and cardiovascular collapse have also been reported, usually when the drug was administered too rapidly. Therapy with intravenous phenytoin or fosphenytoin should be administered cautiously in patients with hypotension or severe myocardial insufficiency, particularly if they are elderly or seriously ill. The rate of injection should not exceed manufacturer recommendations and should be adjusted based on the patient's cardiovascular status. The rate of IV administration for SESQUIENT should not exceed 0.4 mg PE/kg/min in pediatric patients as safety at a faster rate has not been established.

Hydantoin anticonvulsants are primarily metabolized by the liver. Both metabolic activity and plasma protein binding may be significantly altered in patients with liver disease, resulting in elevated drug levels (total and unbound fraction) and increased risk of toxicity. Therapy with hydantoin anticonvulsants should be administered cautiously in patients with impaired hepatic function. Reduced dosages and slower titration may be necessary. In addition, periodic monitoring of liver function is recommended, since the use of anticonvulsants, including hydantoins, has been associated with hepatotoxicity related to drug hypersensitivity. Hepatic failure and death have occurred. Hydantoin therapy should be discontinued and not readministered if evidence of liver damage is observed and felt to be drug-related.

The use of phenytoin has rarely been associated with exacerbation of porphyria. Therapy with phenytoin should be administered cautiously in patients with porphyria. The same precaution should also be observed with other hydantoin anticonvulsants (i.e. ethotoin and mephenytoin) because of their structural and pharmacological similarities to phenytoin.

The use of CNS stimulants can cause psychotic symptoms, suicidal ideation, and aggression, and can exacerbate symptoms of behavior disturbance and thought disorder; CNS stimulants may induce a manic or mixed episode in patients with bipolar disorder. Psychiatric symptoms have been reported in patients with and without history of psychiatric disorders. All patients (particularly those with psychotic or bipolar disorders) should be monitored closely, especially during treatment initiation and at times of dose changes. Extreme caution should be exercised when CNS stimulants are given to patients with a history of psychosis, depression, mania, or bipolar disorder. Prior to initiating therapy, all patients should be screened for risk factors for developing a manic episode (e.g., comorbid or history of depressive symptoms or family history of suicide, bipolar disease, or depression). If any psychiatric symptoms emerge or are exacerbated, treatment suspension should be considered. Some CNS stimulants are contraindicated in patients with marked agitation or anxiety.

The plasma protein binding of phenytoin may be significantly decreased in patients with renal impairment, resulting in elevated free drug concentrations and increased risk of toxicity. This effect is proportional to the degree of renal impairment and stems from quantitative differences in serum albumin as well as qualitative differences in the ability to bind phenytoin. Therapy with phenytoin should be administered cautiously in patients with impaired renal function. Both the therapeutic and toxic plasma total phenytoin levels may be lower than normal in these patients and should be considered in dosing. Alternatively, the monitoring of unbound phenytoin concentrations may be appropriate.

Phenytoin, particularly in high dosages, may cause hyperglycemia by inhibiting insulin release. The drug may also raise serum glucose levels in diabetic patients. Therapy with phenytoin should be administered cautiously in patients with diabetes mellitus, glucose intolerance, or a predisposition to hyperglycemia. Patients with diabetes mellitus should be monitored more closely during phenytoin therapy, and their antidiabetic regimen adjusted accordingly. The same precautions should also be observed with other hydantoin anticonvulsants (i.e. ethotoin and mephenytoin) because of their structural and pharmacological similarities to phenytoin.

The use of acute alcoholic intake may increase phenytoin serum levels while chronic alcoholic use may decrease serum levels. Caution is recommended in alcoholic patients. The same precaution should also be observed with fosphenytoin as this agent is a prodrug of phenytoin.

Patients with a history of drug and/or stimulant abuse should be closely followed during treatment with modafinil. Observe patients for signs of misuse and abuse. Clinical studies indicate modafinil produces psychoactive and euphoric effects/feelings consistent with other CNS stimulants.

Hydantoin anticonvulsants may interfere with folate metabolism and precipitate macrocytosis and megaloblastic anemia, which usually respond to folic acid therapy. These reactions have been fairly uncommon but may be of concern in patients with megaloblastic anemia or folate deficiency receiving hydantoin therapy.

Modafinil is not recommended for use in patients with a history of left ventricular hypertrophy or ischemic ECG changes, chest pain, arrhythmia or other clinically significant manifestations of mitral valve prolapse in association with central nervous system stimulant use. Increased monitoring of heart rate and blood pressure is recommended in patients taking modafinil. Caution is advised in patients with known cardiovascular disease and increased monitoring is recommended in patients with a recent history of myocardial infarction or unstable angina.

Modafinil is not recommended for use in patients with a history of left ventricular hypertrophy or ischemic ECG changes, chest pain, arrhythmia or other clinically significant manifestations of mitral valve prolapse in association with central nervous system stimulant use. Increased monitoring of heart rate and blood pressure is recommended in patients taking modafinil. Caution is advised in patients with known cardiovascular disease and increased monitoring is recommended in patients with a recent history of myocardial infarction or unstable angina.

Modafinil is not recommended for use in patients with a history of left ventricular hypertrophy or ischemic ECG changes, chest pain, arrhythmia or other clinically significant manifestations of mitral valve prolapse in association with central nervous system stimulant use. Increased monitoring of heart rate and blood pressure is recommended in patients taking modafinil. Caution is advised in patients with known cardiovascular disease and increased monitoring is recommended in patients with a recent history of myocardial infarction or unstable angina.

Antiepileptic drugs (AEDs) have been associated with an increased risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Pooled analyses of 199 placebo-controlled clinical studies involving the use of 11 different AEDs showed that patients receiving AEDs had approximately twice the risk of suicidal thinking or behavior compared to patients receiving placebo. AEDs should be administered cautiously in patients with depression or other psychiatric disorders; phentermine-topiramate should be avoided in patients with history of suicidal attempts or active suicidal ideation. The risk of suicidal thoughts and behavior should be carefully assessed against the risk of untreated illness, bearing in mind that epilepsy and many other conditions for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Patients, caregivers, and families should be alert to the emergence or worsening of signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts or behavior. If patients have symptoms of suicidal ideation or behavior, a dosage reduction or treatment discontinuation should be considered.

Phenytoin, particularly in high dosages, may cause hyperglycemia by inhibiting insulin release. The drug may also raise serum glucose levels in diabetic patients. Therapy with phenytoin should be administered cautiously in patients with diabetes mellitus, glucose intolerance, or a predisposition to hyperglycemia. Patients with diabetes mellitus should be monitored more closely during phenytoin therapy, and their antidiabetic regimen adjusted accordingly. The same precautions should also be observed with other hydantoin anticonvulsants (i.e. ethotoin and mephenytoin) because of their structural and pharmacological similarities to phenytoin.

Patients with a history of drug and/or stimulant abuse should be closely followed during treatment with modafinil. Observe patients for signs of misuse and abuse. Clinical studies indicate modafinil produces psychoactive and euphoric effects/feelings consistent with other CNS stimulants.

Hydantoin anticonvulsants may interfere with folate metabolism and precipitate macrocytosis and megaloblastic anemia, which usually respond to folic acid therapy. These reactions have been fairly uncommon but may be of concern in patients with megaloblastic anemia or folate deficiency receiving hydantoin therapy.

Modafinil is not recommended for use in patients with a history of left ventricular hypertrophy or ischemic ECG changes, chest pain, arrhythmia or other clinically significant manifestations of mitral valve prolapse in association with central nervous system stimulant use. Increased monitoring of heart rate and blood pressure is recommended in patients taking modafinil. Caution is advised in patients with known cardiovascular disease and increased monitoring is recommended in patients with a recent history of myocardial infarction or unstable angina.

Modafinil is not recommended for use in patients with a history of left ventricular hypertrophy or ischemic ECG changes, chest pain, arrhythmia or other clinically significant manifestations of mitral valve prolapse in association with central nervous system stimulant use. Increased monitoring of heart rate and blood pressure is recommended in patients taking modafinil. Caution is advised in patients with known cardiovascular disease and increased monitoring is recommended in patients with a recent history of myocardial infarction or unstable angina.

Modafinil is not recommended for use in patients with a history of left ventricular hypertrophy or ischemic ECG changes, chest pain, arrhythmia or other clinically significant manifestations of mitral valve prolapse in association with central nervous system stimulant use. Increased monitoring of heart rate and blood pressure is recommended in patients taking modafinil. Caution is advised in patients with known cardiovascular disease and increased monitoring is recommended in patients with a recent history of myocardial infarction or unstable angina.

Exposure to modafinil is increased in patients with liver dysfunction. In patients with severe liver dysfunction, reduce the dose of modafinil to one-half the dose recommended dose.

Antiepileptic drugs (AEDs) have been associated with an increased risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Pooled analyses of 199 placebo-controlled clinical studies involving the use of 11 different AEDs showed that patients receiving AEDs had approximately twice the risk of suicidal thinking or behavior compared to patients receiving placebo. AEDs should be administered cautiously in patients with depression or other psychiatric disorders; phentermine-topiramate should be avoided in patients with history of suicidal attempts or active suicidal ideation. The risk of suicidal thoughts and behavior should be carefully assessed against the risk of untreated illness, bearing in mind that epilepsy and many other conditions for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Patients, caregivers, and families should be alert to the emergence or worsening of signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts or behavior. If patients have symptoms of suicidal ideation or behavior, a dosage reduction or treatment discontinuation should be considered.

Fosphenytoin injection (Cerebyx, Sesquient) provides a phosphate load of 0.0037 mmol per mg of phenytoin sodium equivalent activity, which should be considered in patients who require phosphate restriction, such as those with severe renal impairment. A new formulation of fosphenytoin (Sesquient) contains an excipient betadex sulfobutyl ether sodium that may accumulate as sulfobutylether beta-cyclodextrin sodium salt in patients with moderate to severe renal impairment. Serum creatinine levels should be closely monitored in patients with severe renal impairment (eGFR 15 to less than 30 mL/min/1.73 m2) and a switch to oral phenytoin should be considered if serum creatinine levels begin to rise.

Phenytoin may decrease serum PBI (protein-bound iodine) levels without associated thyroid disturbance. Free thyroxine concentrations may also be decreased, while resin or red cell T3 uptake values may be increased. Clinicians should be cognizant of these effects when prescribing or administering phenytoin therapy to patients with thyroid disorders.

Phenytoin may interfere with vitamin D metabolism. Hypocalcemia and osteomalacia have been reported. Therapy with phenytoin should be administered cautiously in patients with preexisting vitamin D deficiency. The same precaution should also be observed with other hydantoin anticonvulsants (i.e. ethotoin and mephenytoin) because of their structural and pharmacological similarities to phenytoin.