Drug Interactions between fluconazole and ponesimod

The use of fluconazole has been rarely associated with hepatotoxicity. Reversible idiosyncratic hepatitis, cholestasis and fatal fulminant hepatic failure have been reported, the latter occurring primarily in patients with serious underlying medical conditions and taking multiple concomitant medications. Liver function tests should be performed periodically in patients with preexisting hepatic abnormalities, particularly during prolonged therapy. Treatment should be withdrawn if persistent elevations or worsening of liver enzyme levels occur.

Some azole antifungals have been associated with prolongation of the QT interval on the ECG. Rare cases of QT prolongation and torsade de pointes have been reported during postmarketing experience; such reports usually involved seriously ill patients with multiple confounding risk factors, such as structural heart disease, electrolyte abnormalities, and concomitant medications. These drugs should be administered with caution to patients with potentially proarrhythmic conditions, such as congenital/acquired QT prolongation, cardiomyopathy (especially when heart failure is present), sinus bradycardia, and existing symptomatic arrhythmias. Concomitant use with other medications that have potential to increase the risk of cardiotoxicity should be avoided.

The use of ponesimod may result in a transient decrease in heart rate and atrioventricular (AV) conduction delays, especially during treatment initiation. This drug is not recommended in patients with a history of cardiac arrest, cerebrovascular disease (e.g., TIA, stroke occurring more than 6 months prior to treatment initiation), uncontrolled hypertension, or severe untreated sleep apnea, since significant bradycardia may be poorly tolerated in these patients. The use of this drug in patients with a history of recurrent syncope or symptomatic bradycardia should be based on an overall benefit-risk assessment. Obtain an ECG in all patients to determine whether preexisting conduction abnormalities are present and consult a cardiologist if appropriate. Monitor closely patients taking concurrent therapy with drugs that decrease heart rate (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, and other drugs that may decrease heart rate).

Rare cases of posterior reversible encephalopathy syndrome (PRES) have been reported in patients receiving a sphingosine 1-phosphate receptor modulator. It is recommended to promptly schedule a complete physical and neurological examination and should consider an MRI, if a patient develops any unexpected neurological or psychiatric symptoms/signs, any symptom/sign suggestive of an increase of intracranial pressure, or accelerated neurological deterioration. Delay in diagnosis and treatment may lead to permanent neurological sequelae. Exercise care when using this agent in patients with a history of ischemic stroke or cerebral hemorrhage. Treatment should be discontinued if PRES is suspected.

Macular edema has been reported with the use of sphingosine 1-phosphate (S1P) receptor modulators. Care should be exercised when using these drugs in patients with a history of uveitis and patients with diabetes mellitus as these patients are at increased risk for macular edema. Before starting treatment with these agents, an ophthalmic evaluation of the fundus, including the macula, is recommended in all patients and at any time if vision change is reported during treatment. Patients with a history of uveitis and patients with diabetes mellitus should have regular follow-up examinations of the fundus, including the macula during treatment. Continuation of therapy in patients with macular edema has not been evaluated, therefore, a decision on whether or not to discontinue treatment needs to take into account the potential benefits and risks for the individual patients.

The use of ponesimod may result in a transient decrease in heart rate and atrioventricular (AV) conduction delays, especially during treatment initiation. This drug is not recommended in patients with a history of cardiac arrest, cerebrovascular disease (e.g., TIA, stroke occurring more than 6 months prior to treatment initiation), uncontrolled hypertension, or severe untreated sleep apnea, since significant bradycardia may be poorly tolerated in these patients. The use of this drug in patients with a history of recurrent syncope or symptomatic bradycardia should be based on an overall benefit-risk assessment. Obtain an ECG in all patients to determine whether preexisting conduction abnormalities are present and consult a cardiologist if appropriate. Monitor closely patients taking concurrent therapy with drugs that decrease heart rate (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, and other drugs that may decrease heart rate).

Fluconazole is substantially removed by hemodialysis. Plasma levels of fluconazole has been shown to reduce by 50% following 3 hours of dialysis. Fluconazole should be administered after hemodialysis.

The use of ponesimod may result in a transient decrease in heart rate and atrioventricular (AV) conduction delays, especially during treatment initiation. This drug is not recommended in patients with a history of cardiac arrest, cerebrovascular disease (e.g., TIA, stroke occurring more than 6 months prior to treatment initiation), uncontrolled hypertension, or severe untreated sleep apnea, since significant bradycardia may be poorly tolerated in these patients. The use of this drug in patients with a history of recurrent syncope or symptomatic bradycardia should be based on an overall benefit-risk assessment. Obtain an ECG in all patients to determine whether preexisting conduction abnormalities are present and consult a cardiologist if appropriate. Monitor closely patients taking concurrent therapy with drugs that decrease heart rate (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, and other drugs that may decrease heart rate).

The use of ponesimod may result in increased blood pressure. Care should be exercised when using this drug in hypertensive patients and those at risk for hypertension. It is recommended to monitor blood pressure during treatment and manage it according to clinical practices.

The use of ponesimod may increase the risk of infections, and some serious infections with opportunistic pathogens including viruses have been reported. Prior to treatment, a recent CBC (i.e., within 6 months or after discontinuation of prior therapy) should be available. It is recommended to delay treatment initiation in patients with an active infection until complete resolution. Consider withholding treatment if a patient develops a serious infection, and reassess the benefits and risks prior to reinitiating therapy.

The use of this drug may increase liver transaminases. Ponesimod is not recommended in patients with moderate or severe hepatic impairment (Child-Pugh class B and C). No dosage adjustment is necessary for patients with mild hepatic impairment (Child-Pugh class A). Patients should have liver enzymes checked if they develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, a rash with eosinophilia, or jaundice and/or dark urine during treatment. Obtain transaminase and bilirubin levels, if not recently available (i.e., within the last 6 months) before treatment initiation. Treatment should be discontinued if significant liver injury is confirmed.

Macular edema has been reported with the use of sphingosine 1-phosphate (S1P) receptor modulators. Care should be exercised when using these drugs in patients with a history of uveitis and patients with diabetes mellitus as these patients are at increased risk for macular edema. Before starting treatment with these agents, an ophthalmic evaluation of the fundus, including the macula, is recommended in all patients and at any time if vision change is reported during treatment. Patients with a history of uveitis and patients with diabetes mellitus should have regular follow-up examinations of the fundus, including the macula during treatment. Continuation of therapy in patients with macular edema has not been evaluated, therefore, a decision on whether or not to discontinue treatment needs to take into account the potential benefits and risks for the individual patients.

Rare cases of severe exacerbation of multiple sclerosis (MS), including disease rebound, have been reported after discontinuation of sphingosine 1-phosphate receptor modulator in MS treated patients. The possibility of severe exacerbation of disease should be considered after stopping treatment with these agents. Patients should be observed for a severe increase in disability upon discontinuation and appropriate treatment should be instituted, as required.

Dyspnea has been reported with the use of ponesimod. Dose-dependent reductions in forced expiratory volume over 1 second (FEV1) and reductions in diffusion lung capacity for carbon monoxide have been observed in patients mostly occurring in the first month after treatment initiation. Use with caution in patients with severe respiratory disease such as pulmonary fibrosis, asthma, and chronic obstructive pulmonary disease. Spirometric evaluation of respiratory function should be performed during therapy if clinically indicated.

Fluconazole is primarily eliminated by the kidney. Patients with renal impairment may be at greater risk for adverse effects from fluconazole due to decreased drug clearance. Dosage adjustments are recommended for patients with moderate to severe renal impairment (CrCl <= 50 mL/min) receiving multiple doses of the drug.

The use of ponesimod may result in a transient decrease in heart rate and atrioventricular (AV) conduction delays, especially during treatment initiation. This drug is not recommended in patients with a history of cardiac arrest, cerebrovascular disease (e.g., TIA, stroke occurring more than 6 months prior to treatment initiation), uncontrolled hypertension, or severe untreated sleep apnea, since significant bradycardia may be poorly tolerated in these patients. The use of this drug in patients with a history of recurrent syncope or symptomatic bradycardia should be based on an overall benefit-risk assessment. Obtain an ECG in all patients to determine whether preexisting conduction abnormalities are present and consult a cardiologist if appropriate. Monitor closely patients taking concurrent therapy with drugs that decrease heart rate (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, and other drugs that may decrease heart rate).

The use of ponesimod may result in a transient decrease in heart rate and atrioventricular (AV) conduction delays, especially during treatment initiation. This drug is not recommended in patients with a history of cardiac arrest, cerebrovascular disease (e.g., TIA, stroke occurring more than 6 months prior to treatment initiation), uncontrolled hypertension, or severe untreated sleep apnea, since significant bradycardia may be poorly tolerated in these patients. The use of this drug in patients with a history of recurrent syncope or symptomatic bradycardia should be based on an overall benefit-risk assessment. Obtain an ECG in all patients to determine whether preexisting conduction abnormalities are present and consult a cardiologist if appropriate. Monitor closely patients taking concurrent therapy with drugs that decrease heart rate (e.g., beta-blockers, non-dihydropyridine calcium channel blockers, and other drugs that may decrease heart rate).

Macular edema has been reported with the use of sphingosine 1-phosphate (S1P) receptor modulators. Care should be exercised when using these drugs in patients with a history of uveitis and patients with diabetes mellitus as these patients are at increased risk for macular edema. Before starting treatment with these agents, an ophthalmic evaluation of the fundus, including the macula, is recommended in all patients and at any time if vision change is reported during treatment. Patients with a history of uveitis and patients with diabetes mellitus should have regular follow-up examinations of the fundus, including the macula during treatment. Continuation of therapy in patients with macular edema has not been evaluated, therefore, a decision on whether or not to discontinue treatment needs to take into account the potential benefits and risks for the individual patients.

The use of live attenuated vaccines should be avoided while patients are taking ponesimod and for 1 to 2 weeks after stopping treatment. Patients without a healthcare professional documented history of chickenpox or documentation of a full course of vaccination against varicella zoster virus (VZV) should be tested for antibodies to VZV before the start of treatment. A full course of vaccination for antibody-negative patients with varicella vaccine is recommended prior to treatment initiation. Vaccinations may be less effective if administered during treatment and for up to 1 to 2 weeks after treatment discontinuation. It is recommended to postpone treatment with ponesimod for 4 weeks to allow the full effect of vaccination to occur. If live attenuated vaccine immunizations are required, administer at least 1 month prior to initiation of treatment.