Interactions between Bleomycin and Ponvory

Pulmonary pneumonitis occurs in 10% of patients during bleomycin therapy and 1% progress to pulmonary fibrosis and death. Although pulmonary toxicity is age and dose related, occurring primarily in patients over 70 years of age and in those receiving a total dose > 400 units, it has occurred in younger patients at a lower dose. Extreme caution should be exercised when administering bleomycin in patients with compromised pulmonary function. Patients should be instructed to immediately report symptoms of dyspnea, cough, or congestion. Close clinical monitoring of pulmonary function is recommended.

Bleomycin is primarily eliminated by the kidney. Approximately 60% to 70% of bleomycin is excreted in the urine as active drug. Moderate renal failure reduces elimination to < 20% of the drug. Extreme caution should be exercised when administering bleomycin in patients with existing or predisposition to significantly compromised renal function. Close clinical monitoring of renal function is recommended.

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).

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.

The effect of hepatic insufficiency on the pharmacokinetics of bleomycin has not been evaluated. However, hepatic toxicity, beginning as a deterioration in liver function tests, has been reported. These toxicities may occur at any time after initiation of therapy. Caution and monitoring is advised if bleomycin is used in patients with liver impairment.

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.

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.