Interactions between Cerebyx and Taletrectinib

The fosphenytoin in Cerebyx has a moderate potential interaction with Abnormal Glucose Tolerance.

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 fosphenytoin in Cerebyx has a moderate potential interaction with Alcoholism.

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.

The fosphenytoin in Cerebyx has a moderate potential interaction with Anemia, Folate Deficiency.

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.

Taletrectinib has a moderate potential interaction with Arrhythmia.

Taletrectinib can cause QTc interval prolongation, which can increase the risk for ventricular tachyarrhythmias (e.g., torsades de pointes) or sudden death. In patients with risk factors for QT prolongation such as long QT syndromes, clinically significant bradyarrhythmias, or severe/uncontrolled heart failure, the frequency of monitoring should be adjusted accordingly. Prior to therapy, monitor ECGs and electrolytes in all patients and then periodically as indicated.

The fosphenytoin in Cerebyx has a major potential interaction with Bone Marrow Depression/Low Blood Counts.

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 fosphenytoin in Cerebyx has a moderate potential interaction with Depression.

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.

The fosphenytoin in Cerebyx has a moderate potential interaction with Diabetes Mellitus.

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 fosphenytoin in Cerebyx has a moderate potential interaction with Folic Acid/Cyanocobalamin Deficiency.

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.

Taletrectinib has a moderate potential interaction with Fracture, bone.

Taletrectinib can increase the risk of skeletal fractures. In clinical studies, some fractures occurred in the setting of predisposing factors such as osteoporosis, bone metastasis, and age-related degenerative conditions. There are no data on the effects of taletrectinib on healing of known fractures and risk of future fractures. Promptly evaluate patients with signs/symptoms of fractures (e.g., pain, changes in mobility, deformity).

The fosphenytoin in Cerebyx has a major potential interaction with Heart Disease.

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.

Taletrectinib has a moderate potential interaction with Heart Failure.

Taletrectinib can cause QTc interval prolongation, which can increase the risk for ventricular tachyarrhythmias (e.g., torsades de pointes) or sudden death. In patients with risk factors for QT prolongation such as long QT syndromes, clinically significant bradyarrhythmias, or severe/uncontrolled heart failure, the frequency of monitoring should be adjusted accordingly. Prior to therapy, monitor ECGs and electrolytes in all patients and then periodically as indicated.

The fosphenytoin in Cerebyx has a major potential interaction with Hypotension.

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.

Taletrectinib has a moderate potential interaction with Interstitial Lung Disease.

Taletrectinib can cause severe, life-threatening, or fatal interstitial lung disease (ILD) or pneumonitis. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold therapy in patients with suspected ILD/pneumonitis; dose reduction or permanent discontinuation of taletrectinib may be required based on severity.

The fosphenytoin in Cerebyx has a major potential interaction with Liver Disease.

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.

Taletrectinib has a moderate potential interaction with Liver Disease.

The effect of moderate liver dysfunction (total bilirubin greater than 1.5 to 3 x ULN with any AST) or severe liver dysfunction (total bilirubin greater than 3 x ULN with any AST) on the pharmacokinetics (PK) of taletrectinib is unknown. No clinically significant PK differences were observed based on mild liver dysfunction. Taletrectinib can cause hepatotoxicity, including drug-induced liver injury. Monitor liver function tests including ALT, AST, and total bilirubin at baseline and as recommended by the manufacturer.

Taletrectinib has a moderate potential interaction with Long QT Syndrome.

Taletrectinib can cause QTc interval prolongation, which can increase the risk for ventricular tachyarrhythmias (e.g., torsades de pointes) or sudden death. In patients with risk factors for QT prolongation such as long QT syndromes, clinically significant bradyarrhythmias, or severe/uncontrolled heart failure, the frequency of monitoring should be adjusted accordingly. Prior to therapy, monitor ECGs and electrolytes in all patients and then periodically as indicated.

Taletrectinib has a moderate potential interaction with Neoplasm of Bone.

Taletrectinib can increase the risk of skeletal fractures. In clinical studies, some fractures occurred in the setting of predisposing factors such as osteoporosis, bone metastasis, and age-related degenerative conditions. There are no data on the effects of taletrectinib on healing of known fractures and risk of future fractures. Promptly evaluate patients with signs/symptoms of fractures (e.g., pain, changes in mobility, deformity).

Taletrectinib has a moderate potential interaction with Osteoporosis.

Taletrectinib can increase the risk of skeletal fractures. In clinical studies, some fractures occurred in the setting of predisposing factors such as osteoporosis, bone metastasis, and age-related degenerative conditions. There are no data on the effects of taletrectinib on healing of known fractures and risk of future fractures. Promptly evaluate patients with signs/symptoms of fractures (e.g., pain, changes in mobility, deformity).

The fosphenytoin in Cerebyx has a major potential interaction with Porphyria.

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 fosphenytoin in Cerebyx has a moderate potential interaction with Psychosis.

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.

Taletrectinib has a moderate potential interaction with Pulmonary Impairment.

Taletrectinib can cause severe, life-threatening, or fatal interstitial lung disease (ILD) or pneumonitis. Monitor patients for new or worsening pulmonary symptoms indicative of ILD/pneumonitis. Immediately withhold therapy in patients with suspected ILD/pneumonitis; dose reduction or permanent discontinuation of taletrectinib may be required based on severity.

The fosphenytoin in Cerebyx has a major potential interaction with Renal Dysfunction.

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.

The fosphenytoin in Cerebyx has a moderate potential interaction with Renal Dysfunction.

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.

Taletrectinib has a moderate potential interaction with Renal Dysfunction.

The effect of dialysis or severe renal dysfunction (estimated GFR less than 30 mL/min) on the pharmacokinetics of taletrectinib is unknown. No clinically significant pharmacokinetic differences were observed based on mild or moderate renal dysfunction.

The fosphenytoin in Cerebyx has a moderate potential interaction with Thyroid Disease.

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.

The fosphenytoin in Cerebyx has a moderate potential interaction with Vitamin D Deficiency.

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.