Toprol Xl (metoprolol succinate)

Dosages of metoprolol tartrate and metoprolol succinate are expressed in terms of the tartrate. Since there is no consistent interpatient correlation between the dosage of metoprolol and therapeutic response, dosage must be individualized according to the response of the patient. Blood pressure should be measured near the end of a dosing interval to determine whether satisfactory control is being maintained throughout the day. When patients receiving metoprolol tartrate conventional tablets are switched to metoprolol succinate extended-release tablets, the same daily dosage should be used. If long-term metoprolol therapy is to be discontinued, dosage of the drug should be gradually reduced over a period of 1-2 weeks. (See Cautions: Precautions and Contraindications.)

Metoprolol tartrate and metoprolol succinate are administered orally. Metoprolol tartrate also may be administered IV.

Absorption of metoprolol tartrate may be enhanced by administration with food. The manufacturer recommends that metoprolol tartrate be administered with or immediately following meals. Although administration with meals is not required, metoprolol tartrate should be given in a standardized relation to meals to minimize variance in effect. Food does not appear to affect the bioavailability of metoprolol succinate extended-release tablets.

Metoprolol tartrate may be administered daily as a single dose or in divided doses; metoprolol succinate extended-release tablets should be administered daily as a single dose. If a dose is missed, the patient should take only the next scheduled dose (i.e., the next dose should not be doubled). Metoprolol succinate extended-release tablets are scored and can be divided; however, the tablet or half tablet should be swallowed whole and should not be chewed or crushed.

There is no enhanced messaging for this drug.

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)

Metoprolol/Lumefantrine

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: Lumefantrine may inhibit the metabolism of metoprolol by inhibition of CYP2D6.(1)

CLINICAL EFFECTS: Concurrent administration of lumefantrine and metoprolol may result in elevated metoprolol plasma concentrations, increasing risk of toxicity (bradycardia and hypotension) and decreasing cardioselectivity of metoprolol.(2)

PREDISPOSING FACTORS: Poor metabolizers of CYP2D6 and/or patients taking other CYP2D6 inhibitors are at increased risk for a drug interaction between metoprolol and lumefantrine.

PATIENT MANAGEMENT: The UK manufacturer of artemether-lumefantrine states that the concurrent use of artemether-lumefantrine is contraindicated in patients receiving drugs that are metabolized by CYP2D6, such as metoprolol. (1) The US manufacturer of artemether-lumefantrine states that co-administration of artemether-lumefantrine and medications metabolized by CYP2D6 is not recommended.(3)

DISCUSSION: Lumefantrine has been shown in vitro to inhibit CYP2D6. Because this may be clinically relevant for agents with a low therapeutic index, the manufacturer of artemether-lumefantrine states that the concurrent use of artemether-lumefantrine is contraindicated in patients receiving drugs that are metabolized by CYP2D6, such as metoprolol. (1) The manufacturer of metoprolol states that patients who are poor metabolizers of CYP2D6 may experience much higher plasma concentrations of metoprolol than those with normal CYP2D6 activity, and that co-administration of potent CYP2D6 inhibitors would mimic the pharmacokinetics of CYP2D6 poor metabolizers.(2)

Selected Cyp2d6 Substrates/Mavorixafor

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: Mavorixafor is a strong inhibitor of CYP2D6 and is expected to inhibit the metabolism of agents through this pathway.(1)

CLINICAL EFFECTS: Concurrent use of mavorixafor may result in elevated levels of and toxicity from agents metabolized by CYP2D6.(1)

PREDISPOSING FACTORS: With tricyclic antidepressants, the risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). With anticholinergic agents, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(2)

PATIENT MANAGEMENT: The US manufacturer of mavorixafor states concurrent use with CYP2D6 substrate that are highly dependent on CYP2D6 metabolism is contraindicated.(1) The US manufacturer of doxepin states if concurrent use of doxepin and strong CYP2D6 inhibitors such as mavorixafor is warranted, monitor doxepin plasma concentrations and reduce the doxepin dose based on doxepin plasma concentrations.(5)

DISCUSSION: Mavorixafor (400 mg) increased dextromethorphan (CYP2D6 substrate) maximum concentration (Cmax) and area-under-curve (AUC) by 6-fold and 9-fold, respectively.(1) Selected CYP2D6 substrates linked to this monograph include: aripiprazole, atomoxetine, brexpiprazole, desipramine, deutetrabenazine, dextromethorphan, doxepin, encainide, fenfluramine, metoclopramide, methoxyphenamine, metoprolol, mexiletine, nebivolol, paroxetine, perphenazine, risperidone, tetrabenazine, trimipramine, venlafaxine, and yohimbine.

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)

Selected Cyp1a2 Or Cyp2d6 Substrates/Givosiran

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

MECHANISM OF ACTION: Givosiran interferes with the first and rate-limiting step in hepatic heme biosynthesis, which may lower hepatic heme levels and decrease production and/or activity of cytochrome P450 enzymes.(1,2)

CLINICAL EFFECTS: Concurrent use of givosiran may result in elevated levels of and toxicity from agents metabolized by CYP1A2 or CYP2D6.(1)

PREDISPOSING FACTORS: With tricyclic antidepressants, the risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). With anticholinergic agents, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3)

PATIENT MANAGEMENT: Avoid the concurrent use of givosiran with agents that are sensitive substrates of CYP1A2 or CYP2D6, or CYP1A2 or CYP2D6 substrates with a narrow therapeutic index. If concurrent use is unavoidable, decrease the dose of the CYP1A2 or CYP2D6 substrate and monitor patients for toxicity.

DISCUSSION: A study of 9 patients with acute intermittent porphyria found that givosiran decreased the maximum concentration (Cmax) and area-under-curve (AUC) of caffeine (a CYP1A2 substrate) by 1.3- and 3.1-fold, respectively, compared to caffeine alone. Givosiran also decreased the Cmax and AUC of dextromethorphan (a CYP2D6 substrate) by 2- and 2.4-fold, respectively, compared to dextromethorphan alone.(1,2) Selected CYP2D6 substrates linked to this monograph include: atomoxetine, desipramine, deutetrabenazine, dextromethorphan, doxepin, encainide, methoxyphenamine, metoprolol, nebivolol, nefazodone, paroxetine, perphenazine, risperidone, tetrabenazine, trimipramine, and venlafaxine. Selected CYP1A2 substrates linked to this monograph include: agomelatine, aminophylline, rasagiline, tacrine, theophylline, tizanidine, and yohimbine.

Selected Cyp2d6 Substrates/Desvenlafaxine (>100 Mg)

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

MECHANISM OF ACTION: Desvenlafaxine is considered a weak inhibitor of CYP2D6.(1)

CLINICAL EFFECTS: Concurrent use of desvenlafaxine may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP2D6 pathway.(1) Agents linked to this monograph are: atomoxetine, dapoxetine, deutetrabenazine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, and yohimbine.

PREDISPOSING FACTORS: With perphenazine and tolterodine, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(2)

PATIENT MANAGEMENT: Reduce the dose of CYP2D6 substrates by up to one-half when coadministered with desvenlafaxine 400 mg.(1) Studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 metabolism at the dose of 100 mg daily. CYP2D6 substrates should be dosed at the original level when coadministered with desvenlafaxine 100 mg or lower or when desvenlafaxine is discontinued.(1) The manufacturer of desvenlafaxine does not provide recommendations for use of desvenlafaxine at dosages between 100-400 mg concurrently with CYP2D6 substrates. Monitor for toxicity of the CYP2D6 substrate and consider reducing its dosage.

DISCUSSION: In a study, coadministration of desvenlafaxine 100 mg daily with desipramine (single dose 50 mg) increased desipramine's maximum concentration (Cmax) and area-under-the-curve (AUC)by 25% and 17%.(1) In a study, coadministration of desvenlafaxine 400 mg daily with desipramine (single dose 50 mg) increased desipramine's maximum concentration (Cmax) and area-under-the-curve (AUC)by 50% and 90%.(1) Selected CYP2D6 substrates linked to this monograph are: atomoxetine, dapoxetine, deutetrabenazine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, and yohimbine.

Selected Cyp2d6 Substrates/Panobinostat

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

MECHANISM OF ACTION: Panobinostat is a moderate inhibitor of CYP2D6 and is expected to inhibit the metabolism of agents through this pathway.(1)

CLINICAL EFFECTS: Concurrent use of panobinostat may result in elevated levels of and toxicity from agents metabolized by CYP2D6.(1)

PREDISPOSING FACTORS: With tricyclic antidepressants, the risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). With anticholinergic agents, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(4)

PATIENT MANAGEMENT: Avoid the concurrent use of panobinostat with agents that are sensitive CYP2D6 or CYP2D6 substrates with a narrow therapeutic index. If concurrent use is warranted, monitor patients for toxicity.(1)

DISCUSSION: In a study in 14 subjects with advanced cancer, panobinostat (20 mg daily on Days 3, 5, and 8) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of dextromethorphan (60 mg) by 20-200% and 20-130%, respectively. Dextromethorphan exposures were extremely variable.(1) Selected CYP2D6 substrates linked to this monograph include: atomoxetine, desipramine, deutetrabenazine, dextromethorphan, doxepin, encainide, methoxyphenamine, metoprolol, nebivolol, paroxetine, perphenazine, risperidone, tetrabenazine, trimipramine, venlafaxine, and yohimbine.

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

Beta-Blockers, Oral/Rifamycins

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

MECHANISM OF ACTION: Rifampin is a well recognized enzyme inducer that increases the clearance of many drugs that are metabolized.(1) Beta-blockers that are extensively metabolized may be affected by rifampin.

CLINICAL EFFECTS: Decreased pharmacologic effects of certain beta-blockers.

PREDISPOSING FACTORS: Dose ranging of rifampin did not suggest a dose proportional interaction.(2)

PATIENT MANAGEMENT: Monitor the patient's response to beta-blocker therapy when starting or stopping treatment with rifampin and adjust the dose accordingly.

DISCUSSION: Controlled studies involving healthy volunteers have demonstrated rifampin to increase the clearance of metoprolol and propranolol by more than two fold.(2),(3),(4) Steady state plasma concentrations of propranolol were also reduced. The elimination half-life and protein binding of propranolol were not altered by rifampin. In a study in eight subjects, the concurrent administration of rifampin and carvedilol decreased carvedilol concentrations by 70%.(5)

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/Lidocaine

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

MECHANISM OF ACTION: Decreased cardiac output and hepatic blood flow due to beta-blockers may result in reduced elimination of lidocaine. Inhibition of hepatic microsomal enzymes may also contribute to decreased lidocaine clearance.

CLINICAL EFFECTS: Lidocaine toxicity is more likely to occur when these drugs are used in combination.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The lidocaine dose may need to be adjusted when a beta-blocker is added or discontinued. Clinical signs of lidocaine toxicity and lidocaine plasma levels should be monitored.

DISCUSSION: The effect seems to be more pronounced in the lipid soluble beta-blockers (eg. propranolol, metoprolol).

Beta-Blockers/Mefloquine; Quinidine

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

MECHANISM OF ACTION: Quinidine may inhibit the oxidative metabolism of beta-blockers. In addition, beta-blockers and quinidine exert a negative inotropic action on the heart. Mefloquine is a chemical analogue of quinine which possess 20% of the antifibrillatory action of quinidine. Alterations in electrocardiograms have been observed during mefloquine therapy.

CLINICAL EFFECTS: The pharmacologic effects of certain beta-blockers may be increased during concurrent therapy with quinidine. During concurrent therapy with mefloquine, electrocardiographic abnormalities or cardiac arrest may occur.

PREDISPOSING FACTORS: Cardiac disease.

PATIENT MANAGEMENT: Monitor the response of the patient and adjust the dose of the beta-blocker as needed. The benefits of mefloquine therapy in patients with preexisting cardiac disease should be weighed carefully.

DISCUSSION: Quinidine and beta-blockers have been used therapeutically to treat cardiac arrhythmias; however, they should be used cautiously since quinidine and beta-blockers exert a negative inotropic action on the heart. Quinidine has been associated with an increase in serum metoprolol levels. A reduction in propranolol clearance has been demonstrated in one study, although others have failed to show an interaction between propranolol and quinidine. A patient using timolol eyedrops developed bradycardia following administration of quinidine. There is one report of cardiac arrest, which was successfully treated, in a patient receiving concurrent mefloquine and propranolol. The manufacturer of mefloquine states that concurrent use may produce electrocardiographic abnormalities and cardiac arrest. The manufacturer also recommends weighing the benefits of mefloquine therapy against the risk of adverse effects in patients with cardiac disease.

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/Propafenone

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

MECHANISM OF ACTION: Propafenone increases the serum concentration of certain beta-blockers (e.g., metoprolol and propranolol) by decreasing the first-pass metabolism and by inhibition of metabolism.

CLINICAL EFFECTS: The pharmacologic effect of certain beta-blockers may be increased.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor cardiac function of patients receiving beta-blockers when starting or stopping propafenone. Adjust the dose of the beta-blocker accordingly.

DISCUSSION: Serum concentrations of both metoprolol and propranolol have been found to be increased by concurrent administration of propafenone. A twofold increase in the steady state plasma level of propranolol was measured while metoprolol concentrations increased from two to fivefold.

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)

Metoprolol/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 metoprolol may be decreased.

PREDISPOSING FACTORS: None determined.

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

DISCUSSION: Concurrent administration of metoprolol 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.

Metoprolol/Selected Cyp2d6 Inhibitors

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

MECHANISM OF ACTION: CYP2D6 inhibitors may inhibit the metabolism of metoprolol.(1,2) MECHANISM OF ACTION: CYP2D6 inhibitors may inhibit the metabolism of metoprolol.(1,2) MECHANISM OF ACTION: CYP2D6 inhibitors may inhibit the metabolism of metoprolol.(1,2)

CLINICAL EFFECTS: Concurrent use of CYP2D6 inhibitors may result in elevated levels of and toxicity from metoprolol.(1,2) CLINICAL EFFECTS: Concurrent use of CYP2D6 inhibitors may result in elevated levels of and toxicity from metoprolol.(1,2) CLINICAL EFFECTS: Concurrent use of CYP2D6 inhibitors may result in elevated levels of and toxicity from metoprolol.(1,2)

PREDISPOSING FACTORS: The interaction may be more severe in patients who are ultrarapid metabolizers of CYP2D6.(1,2) PREDISPOSING FACTORS: The interaction may be more severe in patients who are ultrarapid metabolizers of CYP2D6,(1,2) elderly,(3) and on higher doses of beta-blockers.(3) PREDISPOSING FACTORS: The interaction may be more severe in patients who are ultrarapid metabolizers of CYP2D6.(1,2)

PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with metoprolol and inhibitors of CYP2D6. The dosage of metoprolol may need to be adjusted.(1,2) PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with metoprolol and inhibitors of CYP2D6. The dosage of metoprolol may need to be adjusted.(1,2) The effects of rolapitant, a moderate CYP2D6 inhibitor, on CYP2D6 are expected to last at least 28 days after administration.(4) PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with metoprolol and inhibitors of CYP2D6. The dosage of metoprolol may need to be adjusted.(1,2) Rolapitant, a moderate CYP2D6 inhibitor, effects on CYP2D6 are expected to last at least 28 days after administration.(3)

DISCUSSION: In an open-label, randomized, cross-over study in 12 healthy males, celecoxib (200 mg BID) increased the AUC of metoprolol (50 mg) by 64%. One subject experienced a 200% increase.(3) In a randomized, double-blind, cross-over study in 7 healthy subjects, hydroxychloroquine (400 mg) increased the AUC of a single dose of metoprolol by 65%.(4) In a study in 20 Chinese patients with chronic myelogenous leukemia, imatinib (400 mg BID) increased the AUC of metoprolol (100 mg single dose) by 23%. (5) In healthy subjects, ranolazine (750 mg twice daily) increased plasma levels of a single dose of metoprolol (100 mg) by 1.8-fold.(6) CYP2D6 inhibitors include: abiraterone, asunaprevir, berotralstat, bupropion, capivasertib, celecoxib, chloroquine, cinacalcet, citalopram, clomipramine, dacomitinib, diphenhydramine, dronabinol, duloxetine, eliglustat, escitalopram, fedratinib, fluoxetine, hydroxychloroquine, imatinib, levomepromazine, lorcaserin, moclobemide, osilodrostat, paroxetine, quinine, ranitidine, ranolazine, rolapitant, and sertraline. DISCUSSION: In a case report, a patient maintained on metoprolol developed bradycardia following the addition of bupropion.(5) In a study in 20 healthy females, diphenhydramine increased the AUC of metoprolol by 21%. Heart rate reduction increased 29%.(6) In a randomized study in 16 healthy subjects, diphenhydramine decreased metoprolol oral and nonrenal clearance by 2-fold in extensive 2D6 metabolizers. In extensive 2D6 metabolizers, metoprolol-induced effects on heart rate, systolic blood pressure, and aortic blood flow peak velocity were all increased. There were no effects of diphenhydramine in poor metabolizers.(7) Fluoxetine has been shown to inhibit metoprolol metabolism in vitro.(8) There is a case report of severe bradycardia following the addition of fluoxetine to metoprolol.(9) In a 3-way, randomized, cross-over study in healthy subjects, paroxetine (20 mg daily) increased the area-under-curve (AUC) of both S- and R-metoprolol by 3-fold, and 4-fold, respectively, regardless of whether the formulation of metoprolol was immediate release or extended release. Concurrent paroxetine also significantly decreased heart rate and blood pressure when compared to metoprolol alone.(10) In an open-label, randomized, cross-over study in 10 healthy subjects, paroxetine increased the AUC of S-metoprolol and R-metoprolol from an immediate release formulation (50 mg)by 4-fold and 5-fold, respectively. Paroxetine increased the AUC of S-metoprolol and R-metoprolol from an extended release formulation (100 mg) by 3-fold and 4-fold, respectively.(11) In a study in patients with acute myocardial infarction and depression, paroxetine (20 mg daily) increased the AUC of metoprolol 3-fold. Mean heart rate was significantly lower following the addition of paroxetine to metoprolol. Two patients experienced bradycardia and severe orthostatic hypotension.(12) In an open trial in 8 healthy males, paroxetine (20 mg daily) increased the AUC of S-metoprolol and R-metoprolol by 4-fold and 7-fold, respectively.(13) There are case reports of complete atrioventricular block(14) and bradycardia(15) with concurrent metoprolol and paroxetine. A systematic review and meta-analysis of CYP2D6 interactions between metoprolol and either paroxetine or fluoxetine reviewed 9 articles including 4 primary and 2 observational studies as well as 3 case reports. Experimental studies noted paroxetine increased the AUC of metoprolol 3-fold to 5-fold and significantly decreased blood pressure and heart rate. Paroxetine and fluoxetine have shown equipotent inhibitor capacity on CYP2D6. The metabolite, norfluoxetine, is also an inhibitor of CYP2D6.(16) A retrospective cohort study evaluated morbidity in patients on a beta-blocker primarily metabolized by CYP2D6 (e.g., nebivolol, metoprolol, carvedilol, propranolol, labetalol) and started on a strong or moderate CYP2D6-inhibiting antidepressant (e.g., fluoxetine, paroxetine, bupropion, duloxetine). Use of such an antidepressant with a beta-blocker was associated with an increased risk of hospitalization or ED visit due to an adverse hemodynamic event (HR 1.53, 95% CI 1.03-2.81, p=0.04).(3) CYP2D6 inhibitors include: abiraterone, bupropion, celecoxib, cinacalcet, citalopram, dacomitinib, dimenhydrinate, diphenhydramine, duloxetine, escitalopram, fedratinib, fluoxetine, hydroxychloroquine, imatinib, lorcaserin, osilodrostat, paroxetine, ranitidine, ranolazine, rolapitant, and sertraline. 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. DISCUSSION: In a study, citalopram (40 mg daily for 22 days) increased plasma concentrations of metoprolol 2-fold.(4) In a study in healthy subjects, duloxetine (60 mg daily), escitalopram (20 mg daily), and sertraline (100 mg daily) increased the AUC of a single dose of metoprolol by 180%, 89%, and 48-67%, respectively.(5) In a study in 7 healthy subjects, ranitidine (150 mg BID) increased the area-under-curve (AUC) of metoprolol by 50% compared to values obtained 10 months earlier in the same subjects with metoprolol alone.(6) In a study in 6 subjects, pretreatment with ranitidine for 1 week increased the maximum concentration (Cmax) of metoprolol. However, in a follow-up study in 12 healthy subjects, ranitidine had no effect on metoprolol pharmacokinetics when administered concurrently for 1 week.(7) In a study in 6 healthy subjects, ranitidine increased the AUC and Cmax of metoprolol by 50%. There were no changes in metoprolol pharmacodynamics.(8) In a study in healthy subjects, ranitidine increased metoprolol Cmax by about 30%.(9) In a study in 12 healthy males, ranitidine had no effect on the pharmacokinetics or pharmacodynamics of metoprolol.(10) In healthy subjects, ranolazine (750 mg twice daily) increased plasma levels of a single dose of metoprolol (100 mg) by 1.8-fold.(11) A single dose of rolapitant increased dextromethorphan, a CYP2D6 substrate, about 3-fold on days 8 and day 22 following administration. Dextromethorphan levels remained elevated by 2.3-fold on day 28 after single dose rolapitant. The inhibitory effects of rolapitant on CYP2D6 are expected to persist beyond 28 days.(3) CYP2D6 inhibitors include: abiraterone, bupropion, celecoxib, cinacalcet, citalopram, dacomitinib, diphenhydramine, duloxetine, escitalopram, fedratinib, fluoxetine, hydroxychloroquine, imatinib, lorcaserin, osilodrostat, paroxetine, ranitidine, ranolazine, rolapitant, and sertraline. 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.

Metoprolol; Propranolol/Cimetidine

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

MECHANISM OF ACTION: Cimetidine inhibition of CYP2D6 may reduce the metabolism of metoprolol and propranolol.

CLINICAL EFFECTS: Concurrent use of cimetidine may result in increased pharmacologic and toxic side effects of metoprolol and propranolol.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Lower dosages of metoprolol and propranolol may be required in patients receiving cimetidine. When initiating cimetidine in a patient maintained on metoprolol or propranolol, observe the patient for increased beta-blocker effects such as lower heart rate and blood pressure. Consider lower starting doses of metoprolol or propranolol in patients receiving cimetidine. A dosage adjustment of the beta-blocker may be necessary when initiating or discontinuing cimetidine. Since other H-2 antagonists (e.g., ranitidine, famotidine) do not appear to interact, substituting cimetidine with one of these agents may be desirable. However, if a patient is already receiving this combination and is not experiencing adverse effects, substitution is probably not necessary.

DISCUSSION: Concurrent administration of cimetidine (1G/day to 1.2G/day) and propranolol has resulted in approximately a two-fold increase in propranolol plasma concentrations as well as an increase in its area-under-curve (AUC) and half-life after single (80mg) or multiple (160mg/day) doses. The alterations in propranolol levels were seen within 24 to 48 hours.(1-12) Concurrent administration of cimetidine increased the AUC of metoprolol by 60% to 70%.(11-17)

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)

Selected Beta-Blockers/Amiodarone; Dronedarone

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

MECHANISM OF ACTION: The mechanism by which carvedilol, metoprolol, nebivolol, and propranolol and amiodarone produce severe bradycardia and hypotension is due to depressant effects on the sinus and AV node. Since these beta-blockers are cleared by CYP2D6 metabolism and amiodarone is a weak 2D6 inhibitor; amiodarone may decrease their metabolism.(1,3) Dronedarone is a moderate CYP2D6 inhibitor therefore may inhibit the metabolism of carvedilol, metoprolol, nebivolol and propranolol since these beta-blockers are cleared by CYP2D6 metabolism.(2-3)

CLINICAL EFFECTS: The concurrent administration of hepatically metabolized beta-blockers with amiodarone(1) or dronedarone may result in bradycardia and hypotension.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Use low doses of beta-blockers initially. Only increase the dosage of the beta-blocker after ECG verification of good tolerability.(2) Patients receiving a concurrent therapy should be closely monitored for adverse effects, such as bradycardia and hypotension. Patients experiencing this drug interaction should have their beta-adrenergic blocking drug discontinued. Supportive therapy with sympathomimetic agents may be required.

DISCUSSION: In one case report, a patient taking amiodarone developed hypotension and atropine-resistant sinus bradycardia after receiving a single dose of metoprolol. Three hours after receiving the metoprolol dose, the patient experienced dizziness, weakness, and blurred vision.(1) Another report described two patients who exhibited an interaction between amiodarone and propranolol. One patient maintained on amiodarone experienced cardiac arrest after a single oral dose of propranolol. The second patient received intravenous amiodarone followed by 2 doses of oral propranolol and developed severe bradycardia followed by ventricular fibrillation.(4) The stereoselective effect of amiodarone on the pharmacokinetics of racemic carvedilol was evaluated in 106 patients, where 52 received carvedilol monotherapy and 54 received carvedilol with amiodarone. There was no significant differences between the serum concentration to dose ratio between the 2 groups. However, there was an increase in the ratio of S-carvedilol to R-carvedilol. During amiodarone, the concentration of S-carvedilol increased from 3.03 ng/ml to 6.54 ng/ml.(5) Several studies have shown that the addition of carvedilol to congestive heart failure patients currently receiving amiodarone resulted in improved hypotension/dizziness, primary AV block, and aggravated angina.(6-8) Dronedarone increased propranolol and metoprolol (exact dosages not stated) by 1.3-fold and 1.6-fold, respectively.(2) Amiodarone increased metoprolol maximum concentration (Cmax) from 40 mcg/L to 70 mcg/L and area-under-curve (AUC) from 767 mcg x h/L to 1387 mcg x h/L after an amiodarone loading dose of 1.2 g. The interaction was noted to be more pronounced in patients with >/= 2 compared to 1 functional CYP2D6 alleles.(9) Concomitant use of dronedarone and metoprolol were studied in 49 health subjects with four differing CYP2D6 mutations. Thirty-nine were extensive metabolizers of CYP2D6 with Cmax significantly increased from baseline (134.1 ng/mL) on day 13 to 162.6 ng/mL, 195.58 ng/mL, and 180.9 ng/mL after administration of dronedarone 800 mg, 1200 mg, and 1600 mg dose, respectively.(10)

Selected Beta-Blockers/Barbiturates

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

MECHANISM OF ACTION: Induction of hepatic microsomal enzymes by barbiturates decreases bioavailability of oral beta-blockers which are extensively metabolized (e.g., propranolol, metoprolol). Primidone is metabolized to phenobarbital.

CLINICAL EFFECTS: May observe reduced therapeutic response to those beta-blockers metabolized by the liver (e.g., increased pulse rate and increase in systolic and diastolic blood pressures).

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Monitor heart rate and blood pressure when initiating or discontinuing barbiturates and during dosage adjustments. Adjust the dosage of beta-blocker if necessary. If necessary, consider the use of a beta-blocker primarily excreted unchanged by the kidneys (e.g., atenolol, nadolol).

DISCUSSION: The effect of this interaction may be seen in 4 to 5 days after starting barbiturate therapy. If the barbiturate is given for less than 3 days a clinically important interaction is unlikely. Serum concentration of the beta-blocker may increase when the barbiturate is discontinued. Additional documentation is necessary to confirm this potential interaction for individual beta-blockers.

Selected Beta-Blockers/Selected Alpha-Blockers

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

MECHANISM OF ACTION: Alpha-blockers may cause syncope with sudden loss of consciousness secondary to excessive postural hypotension. Following the first dose of an alpha-blocker, compensatory tachycardia helps to prevent or limit syncope. Beta-blockers may inhibit this tachycardia, thereby worsening alpha-blocker induced hypotension.

CLINICAL EFFECTS: The hypotensive effects of an alpha-blocker may be increased in patients on concurrent beta-blocker therapy.

PREDISPOSING FACTORS: Patients may be at increased risk of postural hypotension with concurrent diuretic therapy and those on low-sodium diets.

PATIENT MANAGEMENT: When starting alpha-blocker therapy in patients receiving beta-blockers, consider initiating treatment with a reduced dose of the alpha-blocker. If syncope occurs, provide supportive treatment as necessary. The adverse effect is self limiting and in most cases does not recur after the initial period of therapy or during subsequent dose titration with the alpha-blocker.

DISCUSSION: Beta-blockers increase the acute postural hypotension that frequently follows the first dose of an alpha-blocker. Initiation of beta-blocker therapy in patients that have started taking an alpha-blocker would not be expected to produce acute postural hypotension. Alpha-blockers linked to this interaction include alfuzosin, doxazosin, prazosin, and terazosin. Beta-blockers linked to this interaction include acebutolol, atenolol, betaxolol, bevantolol, levobunolol, metoprolol, nadolol, pindolol, pronethalol, propranolol, and timolol.

Selected Beta-Blockers/Selected Calcium Channel Blockers

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

MECHANISM OF ACTION: Synergistic pharmacologic activity.

CLINICAL EFFECTS: May see an increase in the therapeutic and toxic effects of both drugs. Concurrent use in patients with low heart rates may unmask sick sinus syndrome.

PREDISPOSING FACTORS: Preexisting left ventricular dysfunction and high doses of the beta-blocking agent may predispose patients to adverse responses to this drug combination. Other possible factors include parenteral administration and concurrent administration of other cardio-depressant drugs such as antiarrhythmics.

PATIENT MANAGEMENT: Monitor the patient for signs of increased cardio-depressant effects and hypotension. Adjust the dose accordingly.

DISCUSSION: Coadministration of these classes of drugs may be effective in the treatment of angina pectoris and hypertension. Patients should be screened in order to determine who should receive this combination of agents. The concurrent use of mibefradil and beta-blockers in patients with low heart rates may unmask underlying sick sinus syndrome. 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.

Selected Cyp2d6 Substrates/Desvenlafaxine

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

MECHANISM OF ACTION: Desvenlafaxine is considered a weak inhibitor of CYP2D6.(1)

CLINICAL EFFECTS: Concurrent use of desvenlafaxine may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP2D6 pathway.(1) Agents linked to this monograph are: atomoxetine, dapoxetine, deutetrabenazine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, and yohimbine.

PREDISPOSING FACTORS: With perphenazine and tolterodine, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(2)

PATIENT MANAGEMENT: Reduce the dose of CYP2D6 substrates by up to one-half when coadministered with desvenlafaxine 400 mg.(1) Studies have shown that desvenlafaxine does not have a clinically relevant effect on CYP2D6 metabolism at the dose of 100 mg daily. CYP2D6 substrates should be dosed at the original level when coadministered with desvenlafaxine 100 mg or lower or when desvenlafaxine is discontinued.(1) The manufacturer of desvenlafaxine does not provide recommendations for use of desvenlafaxine at dosages between 100-400 mg concurrently with CYP2D6 substrates. Monitor for toxicity of the CYP2D6 substrate and consider reducing its dosage.

DISCUSSION: In a study, coadministration of desvenlafaxine 100 mg daily with desipramine (single dose 50 mg) increased desipramine's maximum concentration (Cmax) and area-under-the-curve (AUC)by 25% and 17%.(1) In a study, coadministration of desvenlafaxine 400 mg daily with desipramine (single dose 50 mg) increased desipramine's maximum concentration (Cmax) and area-under-the-curve (AUC)by 50% and 90%.(1) Selected CYP2D6 substrates linked to this monograph are: atomoxetine, dapoxetine, deutetrabenazine, dextromethorphan, metoprolol, nebivolol, perphenazine, tolterodine, and yohimbine.

Selected Cyp2d6 Substrates/Terbinafine

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

MECHANISM OF ACTION: Terbinafine is a strong inhibitor of CYP2D6 and may convert patients from the extensive metabolizer to poor metabolizer phenotype for this enzyme.(1)

CLINICAL EFFECTS: Concurrent use of terbinafine may result in increased serum levels and adverse effects of drugs primarily metabolized by or sensitive to changes in the activity of the CYP2D6 metabolic pathway.(1,2)

PREDISPOSING FACTORS: With paroxetine, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3)

PATIENT MANAGEMENT: Terbinafine has a serum half-life of approximately 36 hours, so the maximal effect of this interaction may be delayed for one to two weeks. Extended monitoring may be necessary. Patients receiving therapy with agents primarily metabolized by CYP2D6 need increased monitoring for adverse effects and may need a dose reduction. Plasma level monitoring should be considered in patients receiving flecainide.(4) The effect of terbinafine on CYP2D6 substrates may last for up to four weeks after terbinafine discontinuation. Over time, patients previously stabilized on the combination of terbinafine and a selected CYP2D6 substrate may need an increase in the dose of the CYP2D6 metabolized drug.

DISCUSSION: In a randomized, placebo-controlled trial in 12 healthy subjects, terbinafine (150 mg daily for 6 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of paroxetine (20 mg) by 2.9-fold and 1.9-fold, respectively.(6) In a placebo-controlled trial in 12 healthy males, terbinafine (250 mg for 4 days) increased the Cmax and AUC of a single dose of venlafaxine (75 mg) by 2.67-fold and 4.9-fold, respectively.(7) CYP2D6 substrates linked to this monograph are: dapoxetine, flecainide, metoprolol, nebivolol, paroxetine, perphenazine, propafenone, propranolol, venlafaxine and yohimbine.

Selected Sensitive Cyp2d6 Substrates/Mirabegron

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

MECHANISM OF ACTION: Mirabegron is considered a moderate inhibitor of CYP2D6. FDA defines a moderate inhibitor as a drug which increases the area-under-curve (AUC) of a sensitive substrate 2 to 5 fold.(1,2)

CLINICAL EFFECTS: Concurrent use of mirabegron may lead to increased serum levels and adverse effects of drugs sensitive to inhibition of the CYP2D6 pathway.(1) Agents linked to this monograph are: atomoxetine, clomipramine, desipramine, duloxetine, imipramine, metoprolol, nebivolol, nortriptyline and yohimbine.

PREDISPOSING FACTORS: With desipramine, clomipramine, imipramine and nortriptyline, the risk of seizures may be increased in patients with a history of head trauma or prior seizure; CNS tumor; severe hepatic cirrhosis; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; diabetics treated with oral hypoglycemics or insulin; or with concomitant medications known to lower seizure threshold (antipsychotics, theophylline, systemic steroids). The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3)

PATIENT MANAGEMENT: Mirabegron has a long half-life of approximately 50 hours so extended monitoring over 10 to 13 days may be required to evaluate the full effect of this interaction. The manufacturer of mirabegron recommends appropriate monitoring and dose adjustment if necessary for drugs with a narrow therapeutic index.(1) Weigh the risks versus benefits of mirabegron treatment for overactive bladder symptoms based upon the interacting medication and patient specific characteristics.

DISCUSSION: The manufacturer of mirabegron conducted interaction studies with two sensitive substrates of CYP2D6: desipramine and metoprolol.(1) Mirabegron 160 mg daily for 5 days increased the AUC of a single dose of metoprolol 100mg by 229%. Mirabegron 100 mg daily for 18 days increased the AUC of a single dose of desipramine by 241%.

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• Cardiogenic shock
• Complete atrioventricular block
• Second degree atrioventricular heart block

• Acute asthma attack
• Acute decompensated heart failure
• CYp2d6 poor metabolizer
• Disease of liver
• First degree atrioventricular heart block
• Hypotension
• Peripheral arterial occlusive disease
• Sick sinus syndrome
• Sinus bradycardia
• Wolff-parkinson-white pattern

• Asthma
• Chronic obstructive pulmonary disease
• Depression
• Diabetes mellitus
• Hypoglycemic disorder
• Myasthenia gravis
• Peripheral vascular disease
• Pheochromocytoma
• Psoriasis
• Raynaud's phenomenon

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More Frequent

• Bradycardia
• Depression
• Dizziness
• Hypotension

Less Frequent

• Asthma exacerbation
• Bronchospastic pulmonary disease
• Chronic heart failure
• Peripheral vasoconstriction

Rare or Very Rare

• Acute cognitive impairment
• Agranulocytosis
• Arthralgia
• Blurred vision
• Cardiac arrhythmia
• Chest pain
• Gangrene
• Hallucinations
• Heart block
• Hepatitis
• Idiopathic thrombocytopenic purpura
• Mesenteric artery thrombosis
• Peyronie's disease
• Progressive angina pectoris
• Psoriasiform eruption
• Thrombotic thrombocytopenic purpura
• Tinnitus
• Worsening of chronic heart failure

More Frequent

• Abnormal sexual function
• Diarrhea
• Drowsy
• Dyspnea
• Fatigue
• Pruritus of skin
• Skin rash

Less Frequent

• Constipation
• Insomnia
• Nausea

Rare or Very Rare

• Abdominal pain with cramps
• Alopecia
• Arthritis
• Drug-exacerbated psoriasis
• Dry eye
• Dysgeusia
• Flatulence
• Headache disorder
• Heartburn
• Hyperhidrosis
• Hypoglycemic disorder
• Memory impairment
• Musculoskeletal pain
• Nightmares
• Ocular irritation
• Palpitations
• Paresthesia
• Peripheral edema
• Purpura
• Raynaud's phenomenon
• Rhinitis
• Skin photosensitivity
• Symptoms of anxiety
• Vomiting
• Weight gain
• Xerostomia

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No enhanced messaging available.

Distribution studies in mice have shown that the fetus is exposed to metoprolol when the drug is administered during pregnancy. Although there are no adequate and controlled studies to date in humans, metoprolol has been shown to increase postimplantation loss and to decrease neonatal survival in rats when given at metoprolol succinate dosages (expressed as the tartrate) up to 22 times a daily dosage of 200 mg in a 60-kg patient (on a mg/m2 basis) or metoprolol tartrate dosages up to 55.5 times the maximum recommended human dosage of 450 mg daily. Metoprolol should be used during pregnancy only when clearly needed.

Since metoprolol is distributed into milk, the drug should be used with caution in nursing women. The extent to which metoprolol distributes into milk has not been clearly established, but the amount of drug a nursing infant would ingest (less than 1 mg/L of milk consumed daily) is believed to be too small to be clinically important; however, if a woman receiving metoprolol breastfeeds, the infant should be monitored for potential systemic effects of the drug.

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