Rapiblyk (landiolol HCl)

Dosage of landiolol hydrochloride is expressed in terms of landiolol.

Administer landiolol via IV infusion in a monitored setting, titrating as needed for heart rate control. There are limited data beyond 24 hours of use.

Landiolol is available as a 280-mg single-dose vial of lyophilized powder (equivalent to 300 mg landiolol hydrochloride) that must be reconstituted prior to IV infusion.

Store vials of landiolol powder at 20-25degreesC (excursions permitted between 15-30oC).

Landiolol is compatible with 0.9% sodium chloride injection and 5% dextrose injection.

The prepared solution may be administered via infusion bag (by injecting the reconstituted solution into an empty infusion bag (i.e., no further dilution required)), syringe pump, or direct infusion from the vial (using an appropriate hanging device).

No dosing information is available for this tab.

No dosing information is available for this tab.

In vitro studies indicate that landiolol and its active metabolite (M1) are time-dependent cytochrome p-450 (CYP) 2D6 inhibitors at exposures approximately 50 times the human exposure at the maximum recommended human dose (MRHD).

In vitro studies indicate that landiolol and M1 do not inhibit CYP1A2, CYP2C9, CYP2C19, or CYP3A4.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Beta-Blockers/Arbutamine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Beta-blockers antagonize the effects of arbutamine, a beta-agonist.(1)

CLINICAL EFFECTS: Concurrent use of arbutamine and beta-blockers may attenuate the response to arbutamine.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of arbutamine states that beta-blockers should be withdrawn at least 48 hours prior to the use of arbutamine.(1)

DISCUSSION: Because beta-blockers may antagonize the effects of arbutamine, a beta-agonist, the manufacturer of arbutamine states that beta-blockers should be withdrawn at least 48 hours prior to the use of arbutamine.(1) There is no published documentation for this interaction.

Beta-Blockers/Fenoldopam

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Beta-blockers may inhibit the sympathetic reflex response to fenoldopam.(1)

CLINICAL EFFECTS: Concurrent use of fenoldopam and a beta-blocker may result in unexpected hypotension.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of fenoldopam states that concurrent use with beta-blockers should be avoided. If concurrent use is necessary, caution should be exercised.(1)

DISCUSSION: Because beta-blockers may inhibit the sympathetic reflex response to fenoldopam, the manufacturer of fenoldopam states that concurrent use should be avoided.(1) One set of authors suggests that fenoldopam may be added to labetalol or esmolol therapy in the treatment of hypertensive crisis during acute myocardial ischemia if blood pressure is controlled poorly alone with labetalol or esmolol.(2)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Agents That Cause Bradycardia/Camizestrant

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Camizestrant may cause symptomatic bradycardia. Additional agents that cause bradycardia further increase the risk for symptomatic bradycardia.(1)

CLINICAL EFFECTS: Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of camizestrant recommends avoiding concurrent use of camizestrant and other agents known to cause bradycardia.(1) If combination therapy is unavoidable, monitor heart rate and blood pressure regularly. Monitor heart rate more frequently during the first 30 days of treatment with camizestrant in patient with bradycardia (heart rate less than 60 beats per minute (bpm)) and those on concomitant medications known to lower heart rate.(1) If bradycardia occurs, symptomatic or Grade 2 or above, withhold camizestrant until symptoms resolve. Obtain an ECG to evaluate the etiology of the symptomatic bradycardia. If a contributing concomitant medication is identified, modify the dosage or discontinue the medication as appropriate until bradycardia symptoms resolve and then resume camizestrant. Consider reassessing the heart rate after restarting camizestrant. Permanently discontinue camizestrant for persistent bradycardia.(1) The manufacturer of camizestrant recommends performing an ECG prior to initiating camizestrant, then every week for the first 2 weeks of treatment, and periodically during treatment as clinically indicated.(1)

DISCUSSION: In a clinical trial, bradycardia occurred in 8% of patients on camizestrant. The mean heart rate decrease from baseline was approximately 13 beats per minute with camizestrant, with the maximum decrease observed on Day 15. The median time to onset of adverse reaction was 17 days (range 13 to 283 days) after starting camizestrant. Bradycardia led to dose interruption of camizestrant in 3.9% of patients.(1) Agents that may cause bradycardia and linked to this monograph include: beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, digoxin, and moxonidine.

Agents That Cause Bradycardia/Crizotinib

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Crizotinib may cause symptomatic bradycardia. Additional agents that cause bradycardia further increase the risk for symptomatic bradycardia.(1)

CLINICAL EFFECTS: Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of crizotinib recommends avoiding concurrent use of crizotinib and other agents known to cause bradycardia to the extent possible. If combination therapy is required, monitor heart rate and blood pressure regularly. If bradycardia occurs, withhold crizotinib until heart rate recovers to 60 bpm or above, or patient is asymptomatic. Re-evaluate the use of the concomitant medication. If the concomitant medication is discontinued or its dose is reduced, resume crizotinib at the previous dose upon patient's recovery. If the concomitant medication is not discontinued or dose adjusted, resume crizotinib at a reduced dose upon patient's recovery. If life-threatening bradycardia occurs, discontinue or reduce the dose of the concomitant medication. Upon the patient's recovery, lower the dose of crizotinib to 250 mg daily. Monitor blood pressure and heart rate frequently.(1)

DISCUSSION: Across clinical trials, bradycardia occurred in 13 % of patients on crizotinib, and grade 3 syncope occurred in 2.4 % of patients on crizotinib compared with 0.6 % on chemotherapy.(1) Agents that may cause bradycardia and linked to this monograph include: beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, digoxin, and moxonidine.(1)

Agents That Cause Bradycardia/Fexinidazole

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Fexinidazole has been shown to prolong the QTc interval. Concurrent use with agents that cause bradycardia may increase the risk of QTc prolongation.(1)

CLINICAL EFFECTS: Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of fexinidazole recommends avoiding concurrent use of fexinidazole and other agents known to cause bradycardia.(1) Avoid use of fexinidazole in patients who have a baseline QTcF interval greater than 470 msec, a history of torsade de pointes, congenital long QT syndrome, cardiac arrhythmias, uncompensated heart failure, or family history of sudden death, or uncorrected hypokalemia.(1) If patients are, or need to be, treated with drugs known to induce bradycardia or prolong the QTc interval do not initiate therapy with fexinidazole until such drugs are eliminated from the body (allow a washout period of 5 half-lives for such other drugs). Do not start such drugs until fexinidazole therapy is eliminated (allow a washout period of 7 days).(1)

DISCUSSION: Bradycardia increases the risk of QTc interval prolongation and torsade de pointes.(1) In clinical studies, fexinidazole was associated with a concentration-dependent QTcF prolongation. At recommended therapeutic doses, the mean (upper 90% confidence interval) increase in QTcF is predicted to be 19.0 msec (23.3 msec). The observed increase in QTcF appears to be associated with the M2 (sulfone) metabolite of fexinidazole.(1) Agents that may cause bradycardia and linked to this monograph include: beta-blockers, clonidine, digoxin and moxonidine.(1)

Beta-Blockers/Allergen Immunotherapy

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Beta-blockers may mask early signs and symptoms of anaphylaxis, make the treatment of anaphylaxis more difficult, and increase the severity of the reaction.

CLINICAL EFFECTS: Beta-blockers may reduce a patient's ability to survive a systemic allergic reaction to allergen immunotherapy. Signs and symptoms of anaphylaxis may be masked.

PREDISPOSING FACTORS: Concurrent use of epinephrine with beta-blockers may result in hypertension with reflex bradycardia. Epinephrine resistance in patients with anaphylaxis has been reported.

PATIENT MANAGEMENT: Avoid concomitant administration of immunotherapy and beta-blockers if possible. If patients cannot safely discontinue beta-blockers but have a history of moderate to severe sting-induced anaphylaxis, venom immunotherapy is indicated because the risk of anaphylaxis related to a venom sting is greater than the risk of an immunotherapy-related systemic reaction. In patients taking beta-blockers for whom an acceptable alternative is not available, withholding allergen immunotherapy may be the best option. If both drugs are administered, monitor closely for signs and symptoms of anaphylaxis. Use caution when treating anaphylaxis with epinephrine since response may be poor. Epinephrine administration may worsen anaphylaxis because beta-blockers block the beta effects of epinephrine, which results in predomination of alpha effects. The plasma clearance of epinephrine is decreased. Glucagon may help in the treatment of refractory anaphylaxis in patients receiving beta-blockers.

DISCUSSION: In a case report, a patient taking propranolol was administered pollen extract immunotherapy and immediately developed anaphylaxis. Treatment with epinephrine did not improve symptoms and patient was subsequently intubated.(2) In another case report, a patient taking propranolol was given pollen immunotherapy and developed anaphylaxis. Difficulty in maintaining an adequate blood pressure and pulse continued for several hours despite epinephrine and other supportive measures.(3) There are other case reports of patients taking propranolol with venom immunotherapy that were refractory to treatment.(6-7)

Beta-Blockers/Etrasimod

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Initiation of etrasimod has caused transient decreases in heart rate and atrioventricular conduction delays after the first dose. The first dose has also been associated with heart block. Beta-blockers further increase the risk for symptomatic bradycardia or heart block.(1)

CLINICAL EFFECTS: The heart rate lowering effect of etrasimod is transient and is usually seen with the first dose. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes.(1)

PREDISPOSING FACTORS: Pre-existing cardiovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, history of torsades de pointes, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to etrasimod initiation, or factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia, bradycardia, female gender, or advanced age) may increase risk for cardiovascular toxicity due to etrasimod. Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The prescribing information states etrasimod therapy can be initiated in patients receiving stable doses of beta blocker therapy. Cardiology consultation is recommended before initiating a beta blocker in a patient receiving stable etrasimod treatment.(1)

DISCUSSION: Initiation of etrasimod may result in a transient decrease in heart rate and AV conduction delays. In two studies, after the first dose of etrasimod 2 mg, ulcerative colitis patients saw a mean decrease from baseline in heart rate of 7.2 bpm at hour 3 in UC-1 an hour 2 in UC-2.(1) In UC-1, bradycardia was reported on Day 1 in 1% of etrasimod patients, 0.3% on Day 2 compared to no patients receiving placebo.In UC-2 and UC-3, bradycardia was reported on Day 1 in 2.9% of etrasimod patients, 0.3% on Day 2 compared to no patients receiving placebo. Patients experiencing bradycardia were generally asymptomatic. The few patients with symptomatic bradycardia reported dizziness that resolved without intervention.(1) Beta-Blockers linked to this monograph are: atenolol, betaxolol, bisoprolol, carvedilol, esmolol, labetalol, landiolol, metoprolol, nadolol, nebivolol, propranolol and timolol.

Beta-Blockers/Ponesimod

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Initiation of ponesimod has caused transient decreases in heart rate and atrioventricular conduction delays after the first dose. Decreases in heart rate start within the first hour and maximal decrease in heart rate was seen at approximately 2-4 hours. The first dose has also been associated with heart block. Beta-blockers further increase the risk for symptomatic bradycardia or heart block.(1)

CLINICAL EFFECTS: The heart rate lowering effect of ponesimod is transient and is usually seen with the first dose. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes.(1)

PREDISPOSING FACTORS: Pre-existing cardiovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, history of torsades de pointes, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to siponimod initiation, or factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia, bradycardia, female gender, or advanced age) may increase risk for cardiovascular toxicity due to siponimod. Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The prescribing information states temporary interruption in beta-blocker therapy may be needed before initiation of ponesimod. Beta-blocker therapy can be initiated in patients receiving stable doses of ponesimod.(1) Treatment initiation recommendations include: - Obtain an ECG in all patients to determine whether preexisting conduction abnormalities are present. - In all patients, a dose titration is recommended for initiation of ponesimod treatment to help reduce cardiac effects. - In patients with sinus bradycardia (HR less than 55 bpm), first- or second-degree [Mobitz type I] AV block, or a history of myocardial infarction or heart failure with onset > 6 months prior to initiation, ECG testing and first dose monitoring is recommended. - Since significant bradycardia may be poorly tolerated in patients with history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, or severe untreated sleep apnea, ponesimod is not recommended in these patients. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy. - Use of ponesimod in patients with a history of recurrent syncope or symptomatic bradycardia should be based on an overall benefit-risk assessment. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring. - For patients receiving a stable dose of a beta-blocker, the resting heart rate should be considered before introducing ponesimod treatment. If the resting heart rate is greater than 55 bpm under chronic beta-blocker treatment, ponesimod can be introduced. If resting heart rate is less than or equal to 55 bpm, beta-blocker treatment should be interrupted until the baseline heart-rate is greater than 55 bpm. Treatment with ponesimod can then be initiated and treatment with a beta-blocker can be reinitiated after ponesimod has been up-titrated to the target maintenance dosage. - If a titration dose is missed or if 4 or more consecutive daily doses are missed during maintenance treatment, reinitiate Day 1 of the dose titration and follow titration monitoring recommendations.(1)

DISCUSSION: After the first titration dose of ponesimod the heart rate decrease starts within an hour, and the Day 1 decline is maximal at approximately 2-4 hours. With continued up-titration, further heart rate decreases are seen on subsequent days, with maximal decrease from Day 1-baseline reached on Day 4-5. The highest daily post-dose decrease in absolute hourly mean heart rate is observed on Day 1, with the pulse declining on average 6 bpm. Post-dose declines on the following days are less pronounced. With continued dosing, heart rate starts increasing after Day 6 and reaches placebo levels within 10 days after treatment initiation. In a study, bradycardia occurred in 5.8% of ponesimod-treated patients compared to 1.6% of patients receiving placebo. Patients who experienced bradycardia were generally asymptomatic. Few patients experienced symptoms, including dizziness or fatigue, and these symptoms resolved within 24 hours without intervention.(1) Beta-Blockers linked to this monograph are: atenolol, betaxolol, bisoprolol, carvedilol, esmolol, landiolol, labetalol, metoprolol, nadolol, nebivolol, propranolol and timolol.

Beta-Blockers/Siponimod

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Initiation of siponimod has caused transient decreases in heart rate and atrioventricular conduction delays after the first dose. Decreases in heart rate start within the first hour and maximal decrease in heart rate was seen at approximately 3-4 hours. The first dose has also been associated with heart block. Beta-blockers further increase the risk for symptomatic bradycardia or heart block.(1)

CLINICAL EFFECTS: The heart rate lowering effect of siponimod is transient and is usually seen with the first dose. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes.(1)

PREDISPOSING FACTORS: Pre-existing cardiovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, history of torsades de pointes, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to siponimod initiation, or factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia, bradycardia, female gender, or advanced age) may increase risk for cardiovascular toxicity due to siponimod. Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The prescribing information states temporary interruption in beta-blocker therapy may be needed before initiation of siponimod. Beta-blocker therapy can be initiated in patients receiving stable doses of siponimod.(1) Treatment initiation recommendations include: - Obtain an ECG in all patients to determine whether preexisting conduction abnormalities are present. - In all patients, a dose titration is recommended for initiation of siponimod treatment to help reduce cardiac effects. - In patients with sinus bradycardia (HR less than 55 bpm), first- or second-degree [Mobitz type I] AV block, or a history of myocardial infarction or heart failure with onset > 6 months prior to initiation, ECG testing and first dose monitoring is recommended. - Since significant bradycardia may be poorly tolerated in patients with history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, or severe untreated sleep apnea, siponimod is not recommended in these patients. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy. - Use of siponimod in patients with a history of recurrent syncope or symptomatic bradycardia should be based on an overall benefit-risk assessment. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring. - For patients receiving a stable dose of a beta-blocker, the resting heart rate should be considered before introducing siponimod treatment. If the resting heart rate is greater than 50 bpm under chronic beta-blocker treatment, siponimod can be introduced. If resting heart rate is less than or equal to 50 bpm, beta-blocker treatment should be interrupted until the baseline heart-rate is greater than 50 bpm. Treatment with siponimod can then be initiated and treatment with a beta-blocker can be reinitiated after siponimod has been up-titrated to the target maintenance dosage. - If a titration dose is missed or if 4 or more consecutive daily doses are missed during maintenance treatment, reinitiate Day 1 of the dose titration and follow titration monitoring recommendations.(1)

DISCUSSION: After the first titration dose of siponimod, the heart rate decrease starts within an hour, and the Day 1 decline is maximal at approximately 3-4 hours. With continued up-titration, further heart rate decreases are seen on subsequent days, with maximal decrease from Day 1-baseline reached on Day 5-6. The highest daily post-dose decrease in absolute hourly mean heart rate is observed on Day 1, with the pulse declining on average 5-6 bpm. Post-dose declines on the following days are less pronounced. With continued dosing, heart rate starts increasing after Day 6 and reaches placebo levels within 10 days after treatment initiation. In Study 1, bradycardia occurred in 4.4% of siponimod-treated patients compared to 2.9% of patients receiving placebo. Patients who experienced bradycardia were generally asymptomatic. Few patients experienced symptoms, including dizziness or fatigue, and these symptoms resolved within 24 hours without intervention.(1) Beta-Blockers linked to this monograph are: atenolol, betaxolol, bisoprolol, carvedilol, esmolol, landiolol, labetalol, metoprolol, nadolol, nebivolol, propranolol and timolol.

Beta-Blockers; Av Node Blockers/Fingolimod

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Initiation of fingolimod has a negative chronotropic effect leading to a mean decrease in heart rate of 13 beats per minute (bpm) after the first dose. The first dose has also been associated with heart block. Beta-blockers or agents which slow AV node conduction further increase the risk for symptomatic bradycardia or heart block.

CLINICAL EFFECTS: The heart rate lowering effect of fingolimod is biphasic with an initial decrease usually within 6 hours, followed by a second decrease 12 to 24 hours after the first dose. Symptomatic bradycardia and heart block have been observed. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes. The cause of death in a patient who died within 24 hour after taking the first dose of fingolimod was not conclusive; however a link to fingolimod or a drug interaction with fingolimod could not be ruled out. Beta-Blockers linked to this monograph are: atenolol, betaxolol, bisoprolol, carvedilol, esmolol, landiolol, labetalol, metoprolol, nadolol, nebivolol, propranolol and timolol. AV Node Blocking agents are:digoxin, diltiazem, flecainide, ivabradine, propafenone and verapamil.

PREDISPOSING FACTORS: Pre-existing cardiovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, history of torsades de pointes, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to fingolimod initiation, or factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia, bradycardia, female gender, or advanced age) may increase risk for cardiovascular toxicity due to fingolimod. Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)

PATIENT MANAGEMENT: Fingolimod is contraindicated in patients with Class III/IV heart failure or in patients who have experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA) or decompensated heart failure within the past six months.(1) Patients with pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, or heart block), severe untreated sleep apnea, or a prolonged QTc interval prior to fingolimod initiation should receive cardiologist consultation to evaluate the risks of fingolimod therapy. Patients receiving agents linked to this monograph should have their physician evaluate the possibility of a switch to agents which do not slow heart rate or cardiac conduction. If fingolimod is initiated, the patient should stay overnight in a medical facility with continuous ECG monitoring after the first dose. Correct hypokalemia or hypomagnesemia prior to starting fingolimod. US monitoring recommendations in addition to continuous ECG with overnight monitoring: Check blood pressure hourly. If heart rate (HR) is < 45 beats per minute (BPM) or if the ECG shows new onset of second degree or higher AV block at the end of the monitoring period, then monitoring should continue until the finding has resolved. If patient requires treatment for symptomatic bradycardia, the first dose monitoring strategy should be repeated for the second dose of fingolimod. If, within the first two weeks of treatment one or more fingolimod doses is missed, then first dose procedures are recommended upon resumption. If during weeks 3 and 4 of fingolimod treatment dose is interrupted more than 7 days, then first dose procedures are recommended upon resumption. United Kingdom recommendations(3): Obtain a 12-lead ECG prior to initiating fingolimod therapy. Consult a cardiologist for pretreatment risk-benefit assessment if patient has a resting heart rate less than 55 bpm, history of syncope, second degree or greater AV block, sick-sinus syndrome, concurrent therapy with beta-blockers, Class Ia, or Class III antiarrhythmics, heart failure or other significant cardiovascular disease. Perform continuous ECG monitoring, measure blood pressure and heart rate every hour, and perform a 12-lead ECG 6 hours after the first dose. Monitoring should be extended beyond 6 hours if symptomatic bradycardia or new onset of second degree AV block, Mobitz Type II or third degree AV block has occurred at any time during the monitoring period. If heart rate 6 hours after the first dose is less than 40 bpm, has decreased more than 20 bpm compared with baseline, or if a new onset second degree AV block, Mobitz Type I (Wenckebach) persists, then monitoring should also be continued. If fingolimod treatment is discontinued for more than two weeks, the effects on heart rate and conduction could recur. Thus, first dose monitoring precautions should be followed upon reintroduction of fingolimod.

DISCUSSION: After the first dose of fingolimod, heart rate decrease may begin within an hour. Decline is usually maximal at approximately 6 hours followed by a second decrease 12 to 24 hours after the first dose. The second dose may further decrease heart rate, but the magnitude of change is smaller than the first dose. With continued, chronic dosing, heart rate gradually returns to baseline in about one month.(1,2) Diurnal variation in heart rate and response to exercise are not affected by fingolimod treatment.(2) In a manufacturer sponsored study, fingolimod and atenolol 50 mg daily lowered heart rate 15% more than fingolimod alone. However, additional heart rate lowering was not seen with the combination of extended release diltiazem and fingolimod compared with fingolimod alone.(1)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Beta-Blockers/Anticholinesterases

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Anticholinesterases inhibit plasma cholinesterases and increase cholinergic activity. Use of anticholinesterases may have vagotonic effects on heart rate (e.g. bradycardia). Concurrent use of anticholinesterases and beta-blockers may have additive effects on bradycardia.(1)

CLINICAL EFFECTS: Concurrent use of anticholinesterases and beta-blockers may have additive effects on bradycardia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of anticholinesterases and beta-blockers is not recommended. Additive effects may be increased with cardioselective beta-blockers (e.g. atenolol). Monitor patients closely if concurrent use is warranted.(1)

DISCUSSION: Concurrent use of anticholinesterases and beta-blockers may have additive effects on cardiac conduction and increase the risk of bradycardia.(1) A case report of a 65 year old African American female had a witnessed a presyncopal episode followed by a true syncopal episode with concurrent use of rivastigmine and atenolol. On day 2 of the hospital stay, the patient developed bradycardia with a heart rate in the 40s and sinus pauses greater than 2 seconds. Atenolol was discontinued yet bradycardia persisted. Following discontinuation of rivastigmine, sinus pauses resolved and heart rate returned to normal.(2) A population-based cohort study in Ontario, Canada reviewed the relationship between cholinesterase inhibitor use and syncope-related outcomes over a two year period. Hospital visits for syncope were more frequent in patients receiving cholinesterase inhibitors than controls (31.5 vs 18.6 events per 1000 person-years; adjusted hazard ratio (HR) 1.76; 95% confidence interval (CI) 1.57-1.98). Other syncope-related events were also more common in patients receiving cholinesterase inhibitors than controls: hospital visits for bradycardia (6.9 vs 4.4 events per 1000 person-years; HR 1.69; 95% CI 1.32-2.15); permanent pacemaker insertion (4.7 vs 3.3 events per 1000 person-years; HR 1.49; 95% CI 1.12-2.00); and hip fracture (22.4 vs 19.8 events per 1000 person-years; HR 1.18; 95% CI 1.04-1.34).(3) A population based case-time-control study of 1,009 patients hospitalized for bradycardia within 9 months of using a cholinesterase inhibitor were reviewed for outcomes. Of these patients, 11% required pacemaker insertion during hospitalization and 4% died prior to discharge. With adjustment for temporal changes in drug utilization, hospitalization for bradycardia was associated with recent initiation of a cholinesterase inhibitor drug (adjusted odds ratio (OR) 2.13; 95% CI 1.29-3.51). Risk was similar in patients with pre-existing cardiac disease (adjusted OR 2.25; 95% CI 1.18-4.28) and those receiving negative chronotropic drugs (adjusted OR 2.34; 95% CI 1.16-4.71).(4)

Beta-Blockers/Clonidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Withdrawal of clonidine triggers increased catecholamine release. Beta-blockers inhibit the vasodilation mediated by the beta 2 receptor, leaving the vasoconstriction mediated by the alpha 2 receptor unopposed. In addition, concurrent use is expected to produce additive effects on blood pressure and heart rate requiring standard monitoring precautions.

CLINICAL EFFECTS: Severe hypertension may occur upon abrupt discontinuation of clonidine in patients receiving both clonidine and beta-blockers. In addition, concurrent use is expected to produce additive effects on blood pressure and heart rate requiring standard monitoring precautions.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: In a patient receiving both drugs, discontinuation of the beta-blocker prior to clonidine may decrease the occurrence of rebound hypertension. If clonidine is discontinued first, rebound hypertension can be treated by restarting the clonidine or by the IV administration of phentolamine, phenoxybenzamine or prazosin. When adding either of these agents to the drug regimen of the patient, monitor blood pressure. Since labetalol has both alpha and beta activity, administration of labetalol may prevent rebound hypertension in patients undergoing clonidine withdrawal, although conflicting reports exist. In addition, concurrent use is expected to produce additive effects on blood pressure and heart rate requiring standard monitoring precautions.

DISCUSSION: Increased blood pressure has been observed in patients following: 1) the discontinuation of clonidine in patients receiving beta-blockers, 2) the replacement of clonidine therapy with beta-blockers, 3) the simultaneous discontinuation of both drugs. Conflicting reports exist on the development of increased blood pressure after clonidine withdrawal in patients receiving labetalol. Patients receiving labetalol who are being withdrawn from clonidine should still be closely monitored.

Beta-Blockers/Donepezil; Galantamine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Anticholinesterases like donepezil and galantamine inhibit plasma cholinesterases and increase cholinergic activity. Use of anticholinesterases may have vagotonic effects on heart rate (e.g. bradycardia). Concurrent use of anticholinesterases and beta-blockers may have additive effects on bradycardia.(1,2)

CLINICAL EFFECTS: Concurrent use of donepezil or galantamine with beta-blockers may have additive effects on bradycardia.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Concurrent use of anticholinesterases like donepezil or galantamine with beta-blockers is not recommended. Additive effects may be increased with cardioselective beta-blockers (e.g. atenolol). Monitor patients closely if concurrent use is warranted.(1,2)

DISCUSSION: Concurrent use of anticholinesterases and beta-blockers may have additive effects on cardiac conduction and increase the risk of bradycardia.(1,2) A case report of a 65 year old African American female had a witnessed a presyncopal episode followed by a true syncopal episode with concurrent use of rivastigmine and atenolol. On day 2 of the hospital stay, the patient developed bradycardia with a heart rate in the 40s and sinus pauses greater than 2 seconds. Atenolol was discontinued yet bradycardia persisted. Following discontinuation of rivastigmine, sinus pauses resolved and heart rate returned to normal.(3) A population-based cohort study in Ontario, Canada reviewed the relationship between cholinesterase inhibitor use and syncope-related outcomes over a two year period. Hospital visits for syncope were more frequent in patients receiving cholinesterase inhibitors than controls (31.5 vs 18.6 events per 1000 person-years; adjusted hazard ratio (HR) 1.76; 95% confidence interval (CI) 1.57-1.98). Other syncope-related events were also more common in patients receiving cholinesterase inhibitors than controls: hospital visits for bradycardia (6.9 vs 4.4 events per 1000 person-years; HR 1.69; 95% CI 1.32-2.15); permanent pacemaker insertion (4.7 vs 3.3 events per 1000 person-years; HR 1.49; 95% CI 1.12-2.00); and hip fracture (22.4 vs 19.8 events per 1000 person-years; HR 1.18; 95% CI 1.04-1.34).(4) A population based case-time-control study of 1,009 patients hospitalized for bradycardia within 9 months of using a cholinesterase inhibitor were reviewed for outcomes. Of these patients, 11% required pacemaker insertion during hospitalization and 4% died prior to discharge. With adjustment for temporal changes in drug utilization, hospitalization for bradycardia was associated with recent initiation of a cholinesterase inhibitor drug (adjusted odds ratio (OR) 2.13; 95% CI 1.29-3.51). Risk was similar in patients with pre-existing cardiac disease (adjusted OR 2.25; 95% CI 1.18-4.28) and those receiving negative chronotropic drugs (adjusted OR 2.34; 95% CI 1.16-4.71).(5)

Beta-Blockers/Moxonidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Withdrawal of moxonidine triggers increased catecholamine release. Beta-blockers inhibit the vasodilation mediated by the beta 2 receptor, leaving the vasoconstriction mediated by the alpha 2 receptor unopposed. In addition, concurrent use is expected to produce additive effects on blood pressure and heart rate requiring standard monitoring precautions.

CLINICAL EFFECTS: Severe hypertension may occur upon abrupt discontinuation of moxonidine in patients receiving both moxonidine and beta-blockers. In addition, concurrent use is expected to produce additive effects on blood pressure and heart rate requiring standard monitoring precautions.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If combination therapy with moxonidine and a beta-blocker is to be ceased, the beta-blocker should be stopped first to decrease the risk of rebound hypertension. Moxonidine may be stopped after a few days have elapsed. During cessation of therapy blood pressure should be regularly monitored. If moxonidine is discontinued first, rebound hypertension can be treated by restarting the moxonidine or by the IV administration of phentolamine, phenoxybenzamine or prazosin. Since labetalol has both alpha and beta activity, administration of labetalol may prevent rebound hypertension in patients undergoing moxonidine withdrawal, although conflicting reports exist. When adding either of these agents to the drug regimen of the patient, monitor blood pressure. Concurrent use is expected to produce additive effects on blood pressure and heart rate requiring standard monitoring precautions.

DISCUSSION: Abrupt cessation of combination therapy with moxonidine and a beta-blocker may result in rebound hypertension. Withdrawal of moxonidine may trigger increased catecholamine release. Beta-blockers inhibit the vasodilation mediated by the beta 2 receptor, leaving the vasoconstriction mediated by the alpha 2 receptor unopposed.

Beta-Blockers/Nsaids; Aspirin (Non-Cardioprotective)

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Unknown; however, possibly related to inhibition of prostaglandin by NSAIDs.

CLINICAL EFFECTS: The antihypertensive action of beta-blockers may be decreased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor patient's blood pressure and adjust the dose of the beta-blocker as needed.

DISCUSSION: Concurrent administration of beta-blockers and NSAIDs has been associated with a clinically significant loss in antihypertensive response. The magnitude of the effect of NSAIDs on control of blood pressure by beta-blockers needs to be determined for each anti-inflammatory agent. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Beta-Blockers; Diltiazem; Verapamil/Lacosamide

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Lacosamide may enhance the slow inactivation of voltage-gated sodium channels and may cause dose-dependent bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)

CLINICAL EFFECTS: Concurrent use of lacosamide and agents that affect cardiac conduction (beta-blockers, non-dihydropyridine calcium channel blockers) may increase the risk of bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lacosamide should be used with caution in patients on concomitant medications that affect cardiac conduction, including beta-blockers and non-dihydropyridine calcium channel blockers.(1) If concurrent use is needed, obtain an ECG before lacosamide therapy and after lacosamide dose is titrated to steady-state.(1) Patients should be monitored closely when lacosamide is given intravenously.(1)

DISCUSSION: In a clinical trial in patients with partial-onset seizures, asymptomatic first-degree atrioventricular (AV) block occurred in 4/944 (0.4%) of patient who received lacosamide compared to 0/364 (0%) with placebo.(1) In a clinical trial in patients with diabetic neuropathy, asymptomatic first-degree AV block occurred in 5/1023 (0.5%) of patients who received lacosamide compared to 0/291 (0%) with placebo.(1) Second-degree and complete AV block have been reported in patients with seizures.(1) One case of profound bradycardia was observed in a patient during a 15-minute infusion of 150 mg of lacosamide.(1) Two postmarketing reports of third-degree AV block in patients with significant cardiac history and also receiving metoprolol and amlodipine during infusion of lacosamide injection at doses higher than recommended have been reported.(1) A case report of an 88 year old female taking bisoprolol documented complete AV block after initiation of lacosamide. The patient required pacemaker implementation.(2)

Cardioselective Beta-Blockers/Epinephrine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Concurrent use of beta-blockers also block the beta effects of epinephrine, which results in predomination of alpha effects. The plasma clearance of epinephrine is decreased.

CLINICAL EFFECTS: Concurrent use of epinephrine with beta-blockers may result in hypertension with reflex bradycardia. Epinephrine resistance in patients with anaphylaxis has been reported.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Hypertension and bradycardia are less likely to occur with cardioselective beta-blockers. If both drugs are administered, monitor blood pressure carefully. Use caution when treating anaphylaxis with epinephrine since response may be poor.

DISCUSSION: A 29-year-old male undergoing elective nasal septoplasty developed severe hypertension with a blood pressure of 207/123 mmHg after topical epinephrine (1:1000) was applied to the nasal mucosa. Intravenous metoprolol was administered but the patient went into cardiogenic shock thought to be a result of unopposed alpha stimulation by the combination of epinephrine and metoprolol.(1) A study observed the differences in cardiovascular responses to subcutaneous epinephrine (given to provide hemostasis during scalp incision for craniotomy) between patients who received propranolol vs. metoprolol vs. no pretreatment. While metoprolol prevented the cardiovascular effects of epinephrine infiltration, propranolol pretreatment was associated with a highly significant increase (P less than 0.01) in mean arterial pressure and a significant decrease (P less than 0.05) in heart rate.(2) A double-blind cross-over trial studied the effects of epinephrine infusion during treatment with propranolol vs. metoprolol in 8 hypertensive patients. Patients on propranolol experienced significant increases in blood pressure and systemic vascular resistance (SVR), whereas patients on metoprolol had less increase in systolic blood pressure while the diastolic pressure remained unchanged and SVR decreased.(3) In spontaneously hypertensive rats, epinephrine in combination with pindolol induced remarkable hemodynamic changes (in particular, increase in diastolic blood pressure), which were prevented by phentolamine pretreatment, whereas epinephrine with acebutolol pretreatment induced no significant hemodynamic changes.(4)

Selected Antihypertensive Agents/Selected Maois

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Both MAOIs and antihypertensive agents may increase the risk of postural hypotension.(1,2)

CLINICAL EFFECTS: Postural hypotension may occur with concurrent therapy of MAOIs and antihypertensive agents.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of phenelzine states all patients should be followed closely for symptoms of postural hypotension. Hypotensive side effects have occurred in patients who have been hypertensive and normotensive, as well as hypotensive at initiation of phenelzine.(1) The manufacturer of tranylcypromine states hypotension has been observed most commonly but not exclusively in patients with pre-existing hypertension. Tranylcypromine doses greater than 30 mg daily have a major side effect of postural hypotension and can lead to syncope. Gradual dose titration is recommended to decrease risk of postural hypotension. Combined use with other agents known to cause hypotension have shown to have additive side effects and should be monitored closely.(2) Monitor the patient for signs and symptoms of postural hypotension including dizziness, lightheadedness, or weakness, especially upon standing. Monitor blood pressure as well as orthostatic vitals and adjust antihypertensive therapy, including decreasing the dose, dividing doses, or scheduling doses at bedtime, as needed to maintain goal blood pressure. If blood pressure remains hypotensive, consider decreasing the dose of phenelzine or tranylcypromine. In some cases, discontinuation of one or both agents may be necessary.(3) Normotensive patients on stable antihypertensive therapy who are started on either phenelzine or tranylcypromine may be at increased risk for hypotension. Hypertensive patients on stable phenelzine or tranylcypromine who require antihypertensive therapy would be at decreased risk for hypotension.

DISCUSSION: A review article describes the pharmacology of phenelzine and tranylcypromine as non-selective MAOIs which inhibit both type A and type B substrates. Orthostatic hypotension is described as the most common MAOI side effect and usually occurs between initiation and the first 3-4 weeks of therapy.(3) In a double-blind study, 71 patients were randomized to receive a 4-week trial of either tranylcypromine, amitriptyline, or the combination. The number of patients reporting dizziness at 4 weeks was not different between the three treatment groups (tranylcypromine 52.4%; amitriptyline 65%; combination 66.7%). Blood pressure (BP) assessment noted a significant drop in standing BP in the tranylcypromine group compared to baseline (systolic BP change = -10 mmHg; p<0.02 and diastolic BP change = -9 mmHg; p<0.02). Combination therapy also had a significant drop in standing BP compared to baseline (systolic BP change = -9 mmHg; p<0.02). Patients receiving amitriptyline had no significant change in BP from baseline at 4 weeks. All three groups had a trend toward increasing orthostatic hypotension in BP changes from lying to standing. The change in orthostatic hypotension was significant in the amitriptyline group with an average systolic BP orthostatic drop of -9 mmHg (p<0.05).(4) A randomized, double-blind study of 16 inpatients with major depressive disorder were treated with either phenelzine or tranylcypromine. Cardiovascular assessments were completed at baseline and after 6 weeks of treatment. After 6 weeks, 5/7 patients (71%) who received phenelzine had a decrease in standing systolic BP greater than 20 mmHg from baseline. Head-up tilt systolic and diastolic BP decreased from baseline in patients on phenelzine (98/61 mmHg v. 127/65 mmHg, respectively; systolic change p=0.02 and diastolic change p=0.02). After 6 weeks, 6/9 patients (67%) who received tranylcypromine had a decrease in standing systolic BP greater than 20 mmHg from baseline. Head-up tilt systolic and diastolic BP decreased from baseline in patients on tranylcypromine (113/71 mmHg v. 133/69 mmHg, respectively; systolic change p=0.09 and diastolic change p=0.07).(5) Selected MAOIs linked to this monograph include: phenelzine and tranylcypromine. Selected antihypertensive agents include: ACE inhibitors, alpha blockers, ARBs, beta blockers, calcium channel blockers, aprocitentan, clonidine, hydralazine, moxonidine, and sparsentan.

Selected Antihypertensives And Vasodilators/Apomorphine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Apomorphine causes dose-dependent decreases in blood pressure. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1)

CLINICAL EFFECTS: Concurrent use of antihypertensives and apomorphine may result in orthostatic hypotension with or without dizziness, nausea, or syncope.(1)

PREDISPOSING FACTORS: The risk of orthostatic hypotension may be increased during dose escalation of apomorphine and in patients with renal or hepatic impairment.(1)

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. Counsel patients about the risk of orthostatic hypotension.(1)

DISCUSSION: Healthy volunteers who took sublingual nitroglycerin (0.4 mg) concomitantly with apomorphine experienced a mean largest decrease in supine systolic blood pressure (SBP) of 9.7 mm Hg and in supine diastolic blood pressure (DBP) of 9.3 mm Hg, and a mean largest decrease in standing SBP and DBP of 14.3 mm Hg and 13.5 mm Hg, respectively. The maximum decrease in SBP and DBP was 65 mm Hg and 43 mm Hg, respectively. When apomorphine was taken alone, the mean largest decrease in supine SBP and DBP was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing SBP and DBP was 6.7 mm Hg and 8.4 mm Hg, respectively.(1)

Selected Antihypertensives/Tizanidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Tizanidine is an alpha-2 agonist. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1)

CLINICAL EFFECTS: Concurrent use of antihypertensives and tizanidine may result in hypotension.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. The risk of hypotension may be decreased by careful titration of tizanidine dosages and monitoring for hypotension prior to dose advancement. Counsel patients about the risk of orthostatic hypotension.(1)

DISCUSSION: Severe hypotension has been reported following the addition of tizanidine to existing lisinopril therapy.(2-4)

*Severe sinus bradycardia, sick sinus syndrome, heart block greater than first degree.

*Decompensated heart failure.

*Cardiogenic shock: May precipitate further cardiovascular collapse and cause cardiac arrest.

*Pulmonary hypertension: May precipitate cardiorespiratory decompensation.

*Hypersensitivity reactions, including anaphylaxis, to landiolol or any of the inactive ingredients.

• Cardiogenic shock
• Complete atrioventricular block
• Pulmonary hypertension
• Second degree atrioventricular heart block
• Sick sinus syndrome

• Acute asthma attack
• Chronic heart failure
• Hypotension
• Pheochromocytoma
• Sinus bradycardia
• Wolff-parkinson-white pattern

• Bronchospastic pulmonary disease
• Diabetes mellitus
• Disease of liver
• First degree atrioventricular heart block
• Hyperkalemia
• Hypoglycemic disorder
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Metabolic acidosis
• Peripheral vascular disease
• Prinzmetal angina
• Raynaud's phenomenon

The most common adverse reaction (incidence 9.9%) reported with landiolol hydrochloride in clinical studies was hypotension.

Rare or Very Rare

• Acute cerebral infarction
• Acute myocardial infarction
• Cerebrovascular accident
• Ventricular arrhythmias

More Frequent

• Bradycardia
• Hypotension

Less Frequent

• Headache disorder
• Hypertension
• Hyponatremia
• Nausea
• Pneumonia
• Pulmonary edema
• Tachycardia
• Vomiting

Rare or Very Rare

• Abnormal hepatic function tests
• Acute abdominal pain
• Acute respiratory failure
• Anemia
• Asthma
• Atrial fibrillation
• Atrioventricular block
• Chest discomfort
• Chest pain
• Chills
• Drug-induced hot flash
• Dyspnea
• Erythema
• Fever
• Halitosis
• Hyperbilirubinemia
• Hyperglycemia
• Hypoxia
• Increased lactate acid dehydrogenase
• Injection site sequelae
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Leukopenia
• Low cardiac output
• Muscle spasm
• Right bundle branch block
• Shock
• Sialorrhea
• Thrombocytopenic disorder
• Ventricular tachycardia

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Safety and efficacy of landiolol in pediatric patients from birth to <18 years of age are supported by evidence from adequate and well-controlled studies in adults, with additional pharmacokinetic, pharmacodynamic, and safety data from a descriptive, single-arm, unblinded study that enrolled 60 pediatric patients from birth to <18 years of age. In this study, treatment with landiolol resulted in a >20% reduction in ventricular rate from baseline in patients with atrioventricular reentrant tachycardia (6/7 patients, 85.7%), focal atrial tachycardia (4/8 patients, 50%), junctional ectopic tachycardia (3/12 patients, 25%), and inappropriate sinus tachycardia (10/30 patients, 33.3%).

The available published data on landiolol use in pregnant women are insufficient to inform a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Landiolol exposure was limited to a single injection at the time of Cesarean delivery in a small clinical trial. With other beta-blockers, neonatal bradycardia, hypoglycemia, and respiratory depression have been observed when administered near the time of delivery.

In pregnant rats, landiolol was distributed to the placenta and fetus following administration. In animal reproduction studies, no embryo-fetal toxicity was observed in rats or rabbits during organogenesis following landiolol exposure approximately 2.7-times the human exposure at the maximum recommended human dose (MHRD).

Landiolol crosses the placenta in rats. Neonates born to mothers who are receiving landiolol during pregnancy may be at increased risk for hypotension, hypoglycemia, bradycardia, and respiratory depression. Monitor neonates exposed to landiolol during pregnancy and labor for hypotension, hypoglycemia, bradycardia, and respiratory depression, and manage accordingly.

It is not known whether landiolol is distributed into human milk. Effects of the drug on breastfed infants or milk production are also not known. However, other beta-blockers are detected in human milk, and landiolol has been identified in the milk of lactating rats; therefore, it is likely that the drug is present in human milk.

Monitor the breastfed infant for bradycardia and other symptoms of beta-blockade, such as lethargy (hypoglycemia).

The manufacturer makes no specific recommendations for geriatric patients >=65 years of age. In general, dosage selection should start at the low end of the dosing range.

Clinical studies did not include sufficient numbers of patients >=65 years of age to determine whether they respond differently from younger subjects. In general, due to the greater frequency of decreased hepatic, renal, and/or cardiac function, and concomitant disease or other drug therapy, dosage selection for an elderly patient should be cautious, usually starting at the low end of the dosing range.