Drug Interactions between fedratinib and modafinil

Grapefruit juice can increase the blood levels of fedratinib. This may increase the risk of serious side effects such as Wernicke's encephalopathy, a potentially fatal condition of the brain associated with thiamine (vitamin B1) deficiency; low blood cell counts, which can lead to anemia, bleeding, and infections; severe diarrhea, nausea, and vomiting; problems in the liver or pancreas; and development of other cancers. You should avoid the consumption of grapefruit and grapefruit juice during treatment with fedratinib. You may take the medication with or without food, but taking it with a high-fat meal may help reduce nausea and vomiting. Talk to your doctor or pharmacist if you have questions on how to take this or other medications you are prescribed. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

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

In a major safety study of a Janus kinase (JAK) inhibitor, tofacitinib, in rheumatoid arthritis patients 50 years and older with at least 1 cardiovascular risk factor, higher rates of all-cause mortality (including sudden cardiovascular death) and major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke) were observed with the JAK inhibitor when compared with tumor necrosis factor (TNF) blockers. Patients who were current or past smokers had an additional increased risk. Based on a shared mechanism of action, this risk should be considered for other JAK inhibitors, including baricitinib, upadacitinib, ruxolitinib, fedratinib, ritlecitinib, deuruxolitinib, and pacritinib. Consider the benefits and risks for each individual patient prior and during treatment with JAK inhibitors, especially in patients with other cardiovascular risk factors, history of cardiovascular events, and patients who are current or past smokers. Patients should be informed about the symptoms of serious cardiovascular events and what to do if they occur.

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.

Gastrointestinal (GI) toxicities are the most frequent adverse reactions reported with fedratinib; diarrhea, nausea, and vomiting occurred in more than half of patients. The median time to onset was 1 day, with 75% of cases occurring within 2 weeks of initiating therapy. Consuming a high-fat meal with fedratinib may reduce GI adverse events. Prophylactic antiemetic therapy (e.g., 5-HT3 receptor antagonists) should be considered. Treat diarrhea with antidiarrheals at the first onset of symptoms. For Grade 3 or higher nausea, vomiting, or diarrhea not responsive to supportive measures within 48 hours: Interrupt this drug until resolved to Grade 1 or less or baseline; restart dose at 100 mg/day below the last given dose.

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 pharmacokinetics of fedratinib have not been evaluated in patients with severe hepatic impairment (total bilirubin > 3 times ULN and any AST), and its use should be avoided on these patients.

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.

Malignancies (including lymphomas and solid tumors) have been reported in patients treated with tofacitinib, baricitinib, upadacitinib, deuruxolitinib and other Janus kinase (JAK) inhibitors used to treat inflammatory conditions. Patients who are current or past smokers are at additional increased risk of malignancies. Based on a shared mechanism of action, this risk should be considered for other JAK inhibitors, including ruxolitinib, pacritinib, and fedratinib. Before starting or continuing therapy, the benefits and risks for the individual patient should be considered, especially in patients with a known malignancy (other than successfully treated nonmelanoma skin cancer), patients who develop a malignancy during therapy, and patients who are current or past smokers. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

In a major safety study of a Janus kinase (JAK) inhibitor, tofacitinib, in rheumatoid arthritis patients 50 years and older with at least 1 cardiovascular risk factor, higher rates of all-cause mortality (including sudden cardiovascular death) and major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke) were observed with the JAK inhibitor when compared with tumor necrosis factor (TNF) blockers. Patients who were current or past smokers had an additional increased risk. Based on a shared mechanism of action, this risk should be considered for other JAK inhibitors, including baricitinib, upadacitinib, ruxolitinib, fedratinib, ritlecitinib, deuruxolitinib, and pacritinib. Consider the benefits and risks for each individual patient prior and during treatment with JAK inhibitors, especially in patients with other cardiovascular risk factors, history of cardiovascular events, and patients who are current or past smokers. Patients should be informed about the symptoms of serious cardiovascular events and what to do if they occur.

Serious and fatal encephalopathy, including Wernicke's disease, has occurred in patients treated with fedratinib. Wernicke's encephalopathy is a neurologic emergency. Assess thiamine levels in all patients prior to starting treatment, periodically during treatment, and as clinically indicated. Do not start fedratinib in patients with thiamine deficiency; replete thiamine prior to treatment initiation. If encephalopathy is suspected, immediately discontinue fedratinib and initiate parenteral thiamine. Patients who develop any change in their mental status during treatment, including confusion or memory impairment, should be evaluated for potential encephalopathy (e.g., neurologic examination, thiamine level assessment, imaging). Monitor until symptoms resolve or improve and thiamine levels normalize.

Thrombosis (including deep venous thrombosis, pulmonary embolism, cerebral venous sinus thrombosis, and arterial thrombosis) has occurred in patients treated for inflammatory conditions with Janus kinase (JAK) inhibitors, including baricitinib, tofacitinib, deuruxolitinib and upadacitinib. Many of these adverse events were serious and some resulted in death. Based on a shared mechanism of action, this risk should be considered for other JAK inhibitors, including ruxolitinib, fedratinib, and pacritinib. In general, JAK inhibitors should be avoided in patients who may be at increased risk of thrombosis. Tofacitinib should be used at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response when treating ulcerative colitis. If symptoms of thrombosis occur in any patients receiving JAK inhibitors, treatment should be discontinued and patients should be evaluated promptly and treated appropriately.

Gastrointestinal (GI) toxicities are the most frequent adverse reactions reported with fedratinib; diarrhea, nausea, and vomiting occurred in more than half of patients. The median time to onset was 1 day, with 75% of cases occurring within 2 weeks of initiating therapy. Consuming a high-fat meal with fedratinib may reduce GI adverse events. Prophylactic antiemetic therapy (e.g., 5-HT3 receptor antagonists) should be considered. Treat diarrhea with antidiarrheals at the first onset of symptoms. For Grade 3 or higher nausea, vomiting, or diarrhea not responsive to supportive measures within 48 hours: Interrupt this drug until resolved to Grade 1 or less or baseline; restart dose at 100 mg/day below the last given dose.

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.

Adverse hematologic effects including neutropenia, thrombocytopenia, and anemia have been associated with the use of fedratinib. It is recommended to modify the starting dose in patients with a baseline platelet count (PLT) less than 50 x 10(9)/L. Therapy should be interrupted until grade 4 thrombocytopenia, grade 3 thrombocytopenia with active bleeding, OR grade 4 neutropenia has normalized to grade 2 or lower (or baseline), then restart treatment at 100 mg/day below the last given dose. Fedratinib dose reductions should be considered in patients who become dependent on red blood cell transfusions. CBC counts should be monitored at baseline and every 3 months thereafter; treatment should be modified based on PLT levels and active bleeding. Caution is recommended in patients who may be at increased risk.

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.

Adverse hematologic effects including neutropenia, thrombocytopenia, and anemia have been associated with the use of fedratinib. It is recommended to modify the starting dose in patients with a baseline platelet count (PLT) less than 50 x 10(9)/L. Therapy should be interrupted until grade 4 thrombocytopenia, grade 3 thrombocytopenia with active bleeding, OR grade 4 neutropenia has normalized to grade 2 or lower (or baseline), then restart treatment at 100 mg/day below the last given dose. Fedratinib dose reductions should be considered in patients who become dependent on red blood cell transfusions. CBC counts should be monitored at baseline and every 3 months thereafter; treatment should be modified based on PLT levels and active bleeding. Caution is recommended in patients who may be at increased risk.

Adverse hematologic effects including neutropenia, thrombocytopenia, and anemia have been associated with the use of fedratinib. It is recommended to modify the starting dose in patients with a baseline platelet count (PLT) less than 50 x 10(9)/L. Therapy should be interrupted until grade 4 thrombocytopenia, grade 3 thrombocytopenia with active bleeding, OR grade 4 neutropenia has normalized to grade 2 or lower (or baseline), then restart treatment at 100 mg/day below the last given dose. Fedratinib dose reductions should be considered in patients who become dependent on red blood cell transfusions. CBC counts should be monitored at baseline and every 3 months thereafter; treatment should be modified based on PLT levels and active bleeding. Caution is recommended in patients who may be at increased risk.

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.

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.

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.

Pancreatitis occurred in patients receiving fedratinib. It is recommended to monitor lipase and amylase prior to the start of therapy with fedratinib and periodically thereafter as clinically indicated. Therapy should be interrupted until grade 3 or higher elevations in amylase and/or lipase levels resolve to grade 1 or less (or baseline), then restart treatment at 100 mg/day below the last given dose. Care is recommended when using this agent in patients at risk.

Due to potential increase of exposure, patients with preexisting-existing moderate renal impairment require more intensive safety monitoring, and if necessary, dose modifications based on adverse reactions when treated with fedratinib. Reduce fedratinib dose when administered to patients with severe renal impairment (CrCl 15 mL/min to 29 mL/min by Cockcroft-Gault). No modification of the starting dose is recommended for patients with mild to moderate renal impairment (CrCl 30 mL/min to 89 mL/min by Cockcroft-Gault).