Timolol Maleate (timolol maleate)

Reductions in heart rate and blood pressure should be monitored as a guide for determining optimum dosage of timolol maleate. If long-term timolol 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.)

In patients with renal or hepatic impairment, doses and/or frequency of administration of timolol maleate must be modified in response to the degree of renal or hepatic impairment.

Timolol maleate is administered orally.

Timolol maleate shares the drug interaction potential of other nonselective beta-adrenergic blocking agents (beta-blockers), and the usual precautions of these agents should be observed when concomitant therapy with other drugs is considered. In addition to the drug interactions that follow, interactions described for other nonselective beta-blockers are likely with timolol. For additional information on the drug interaction potential of timolol, see Drug Interactions, in Propranolol Hydrochloride 24:24.

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

Beta-Blockers/Arbutamine

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

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

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

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of arbutamine states that beta-blockers should be withdrawn at least 48 hours prior to the use of arbutamine.(1)

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the effects of arbutamine, a beta-agonist, the manufacturer of arbutamine states that beta-blockers should be withdrawn at least 48 hours prior to the use of arbutamine.(1) There is no published documentation for this interaction.

Beta-Blockers/Fenoldopam

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

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

Agents That Affect Catecholamines/Iobenguane I 123

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

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with imaging completed with iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores prior to imaging with iobenguane. Before imaging with iobenguane, discontinue agents that affect catecholamines for at least 5 biological half-lives, as clinically tolerated.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine)

Agents That Affect Catecholamines/Iobenguane I 131

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

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may impact the dosimetry calculations or effectiveness of iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores for at least 5 half-lives before administration of either the dosimetry or a therapeutic dose of iobenguane. Do not administer these drugs until at least 7 days after each iobenguane dose.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine) - calcium channel blockers

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 (NONSELECTIVE)/Methyldopa

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

MECHANISM OF ACTION: Unopposed alpha-adrenergic vasoconstriction produced by alpha-methylnorepinephrine in the presence of beta-blockade.

CLINICAL EFFECTS: Severe hypertension.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor blood pressure during concomitant administration of methyldopa and a nonselective beta-blocker. If hypertension occurs, treatment with phentolamine should be considered.

DISCUSSION: Although methyldopa and propranolol have been used together to treat hypertension, severe increases in blood pressure, including death in one patient, has been reported during administration of these drugs. In addition, methyldopa alone has been reported to cause paradoxical hypertension. Additional studies are needed to define the specific population at risk.

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)

Non-Cardioselective Beta-Blockers/Beta-2 Agonists

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

MECHANISM OF ACTION: Non-cardioselective beta-blockers and beta-2 agonists may antagonize the effects of each other.

CLINICAL EFFECTS: Diminished response to either the beta-agonist, beta-blocker, or both may occur. Beta-blockers may also induce bronchospasm.

PREDISPOSING FACTORS: Patients receiving beta-2 agonists for the treatment of asthma may be more at risk for bronchospasm.

PATIENT MANAGEMENT: If possible, avoid beta-blocker therapy in asthmatic patients requiring beta-2 agonist therapy. If beta-blocker therapy is required, use a cardio-selective beta-blocker. For timolol ophthalmic drops, counsel patients to apply pressure to the inner corner of the eye after administration to prevent systemic absorption. Monitor patients for decreased effects of either agent, such as increased need for/use of beta-2 agonists or increased heart rate or blood pressure.

DISCUSSION: Many patients with asymptomatic or mild reactive airways disease tolerate beta-blockers well. Most patients with COPD do not have bronchospastic component to their illness and may be given beta-blockers. Heart failure treatment guidelines recommend beta-blockers in the presence of COPD. Non-selective beta-blockers have been shown to have a negative effect on lung function (FEV1) and airway hyperresponsiveness (AHR) in patients with asthma and COPD.(1) An open-label study using the nonselective beta blocker nadolol showed no effect on salbutamol in 10 patients with mild asthma not on controller therapy.(2) A study in 8 healthy men showed that long acting propranolol (160 mg) only effected airway dilation at the 200 mcg salbutamol dose. The 800 mcg and 1600 mcg dose were unaffected. However, penbutolol prevented any significant airway dilation with all doses of salbutamol.(3) In a double blind, three-way, crossover study, 44% (7/16 patients) of patients taking metoprolol showed a greater than 20% decrease in FEV1 compared to 19% (3 patients) after dilevalol and 6% (1 patient) after placebo. Dilevalol and metoprolol significantly inhibited isoproterenol response compared to placebo.(4) A double-blind, randomized, crossover study in 10 asthmatic patients showed that intravenous propranolol produced marked symptomatic bronchoconstriction. Only a slight but significant inhibition of bronchomotor sensitivity to isoproterenol was noted during esmolol infusion.(5) In 18 patients with reversible bronchial asthma, labetalol caused a significant increase in FEV1 and metoprolol caused a significant decrease in FEV1. Concurrent administration of isoproterenol and labetalol caused a further increase in FEV1. The effect of isoproterenol was decreased by metoprolol (100, 200mg).(6) In one study propranolol (0.06mg/kg IV) was shown to almost completely block the effects of isoproterenol in asthmatics. Metoprolol (0.12mg/kg IV) did not affect isoproterenol.(7) Studies have shown that cardioselective beta-blockers are safe for patients with asthma and COPD.(8,9,10) Nebivolol and celiprolol significantly decreased FEV1. Inhalation of albuterol (up to 800mcg) significantly improved FEV1, but the values after nebivolol and celiprolol administration were lower than the initial values.(11) Administration of metoprolol did not cause any respiratory problems in 9 asthmatic patients. There was no significant difference between the metoprolol and placebo groups in the respiratory response to an isoproterenol aerosol in 24 asthmatic patients.(12) Eight male asthmatic patients were given 10 mg bisoprolol, 20 mg bisoprolol, and 100 mg metoprolol. Both bisoprolol and metoprolol caused bronchoconstriction measured by a significant fall in PEFR (peak expiratory flow rate). Terbutaline was able to reverse bronchoconstriction in all patients.(13) A double blind, placebo-controlled study analyzed the use of atenolol 100mg, metoprolol 100mg, or acebutolol 400 mg in 8 asthmatic patients before and after exercise. All three drugs reduced significantly FEV1 and PEFR. Administration of terbutaline improved all respiratory indices.(14) A double-blind crossover trial in 10 asthmatic patients showed that a single IV dose of atenolol 3mg caused slight impairment of ventilatory function. A dose of salbutamol by inhalation was able to reverse the bronchial effect of atenolol.(15) Propranolol (80mg/day), oxprenolol (80mg/day), atenolol (100mg/day), and celiprolol 200mg/day were given to 10 asthmatic patients in a randomized, crossover design with a two week washout period between each drug. The non-beta 1 selective beta blockers (propranolol, oxprenolol) caused a significant reduction in FEV1 and inhibited the bronchodilator response to inhaled salbutamol. Atenolol and celiprolol (beta1 selective beta blockers) did not significantly affect respiratory function or antagonize salbutamol effects.(16) A double blind, randomized, within patient, placebo-controlled study compared the cardioselective beta-blocker atenolol to the non-selective propranolol. Atenolol caused a significantly less drop in FEV1 compared to propranolol. The effect of isoprenaline plus the beta blockers were also studied. Both atenolol and propranolol effected isoprenaline FEV1 dose response curves but the greatest displacement was seen with propranolol.(17) The pulmonary effects of celiprolol 200 mg, celiprolol 400mg, propranolol 40mg, atenolol 100 mg were evaluated in 34 asthmatic patients. Propranolol and atenolol caused significant reductions in pulmonary function. Propranolol pretreatment caused a significant reduction in the effect of the bronchodilator. Celiprolol did not antagonize the bronchodilators.(18) A double-blind, placebo controlled, randomized, crossover design study studied the effects of propranolol 80mg or celiprolol 200 or 400mg on pulmonary function. Propranolol produced a significant decrease in FEV1 and FVC. Celiprolol and placebo had similar results. The effect of aerosolized terbutaline was also measured. Even at supratherapeutic doses, terbutaline was unable to restore pulmonary function parameters to baseline levels after treatment with propranolol. Terbutaline caused further bronchodilation after administration of celiprolol.(19) Eleven asthmatic patients showed significant bronchoconstriction in small airways after propranolol 40mg and pindolol 2.5mg in a double blind, randomized trial. Large airways only showed bronchoconstriction with propranolol. Terbutaline 0.5mg subcutaneous was given after pretreatment with propranolol and pindolol. The bronchodilator effect of terbutaline on large airways was diminished after both propranolol and timolol.(20)

Non-Cardioselective Beta-Blockers/Epinephrine

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

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

DISCUSSION: In a study of 6 subjects, an increase in mean arterial pressure (MAP) of 15.1% (p < 0.05) was observed after an infusion of epinephrine (10 ng/kg/min) followed by an intravenous injection of propranolol (40 mcg/kg). In addition, plasma clearance of epinephrine decreased to 54.7% of the control value after the dose of propranolol.(1) In another study of 6 subjects, patients were intravenously administered 15 mcg epinephrine, followed by propranolol 0.04 mg/kg, and then another dose of epinephrine. A mean decrease in heart rate of 37% (p < 0.001) was observed following the second dose of epinephrine.(2) In a study in 10 healthy subjects, an increase in MAP was observed after infusion of epinephrine (5 mcg/min) followed by infusion of propranolol (10 mg).(5) In a study in 1 healthy subject, marked bradycardia and atrioventricular block occurred after administration of propranolol (40 mg orally) with epinephrine (17 mcg/min intravenously).(6) In a study in 7 healthy subjects, and increase in MAP (8% increase in systolic blood pressure, 10% increase in diastolic blood pressure) was observed after injection of epinephrine (45 mcg in lidocaine) in to the maxilla after pretreatment with pindolol (5 mg).(7) A retrospective analysis of sinus surgery patients found that 9.1% had exaggerated intraoperative hypertensive events during the first surgical hour (defined as relative increase greater than 20% of systolic blood pressure or single systolic blood pressure value above 200 mmHg). Subjects with established beta blockade were found to be three times as likely to experience an exaggerated hypertensive event during the first intraoperative hour.(8) In a study, intraoral injection with 2% lidocaine containing epinephrine (45 mcg) after pretreatment with pindolol (5 mg) resulted reduced stroke volume, increase in afterload, decreased myocardial contractility, decreased heart rate, and an increase in blood pressure.(9) In a study in 8 subjects, a comparison of propranolol (80 mg three times daily) or metoprolol (100 mg three times daily) with epinephrine (8 mcg/min for 6 minutes) showed that propranolol significantly increases MAP while metoprolol, a beta1-selective beta-blocker, does not.(10) There are several case reports of significant hypertension with reflex bradycardia.(9-12) In some of these case reports patients had strokes.(12)

Non-Cardioselective Beta-Blockers/Salmeterol

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

MECHANISM OF ACTION: Non-cardioselective beta-blockers and beta-2 agonists may antagonize the effects of each other.

CLINICAL EFFECTS: Diminished response to either the beta-agonist, beta-blocker, or both may occur. Beta-blockers may also induce bronchospasm.

PREDISPOSING FACTORS: Patients receiving beta-2 agonists for the treatment of asthma may be more at risk for bronchospasm.

PATIENT MANAGEMENT: If possible, avoid beta-blocker therapy in asthmatic patients requiring beta-2 agonist therapy. If beta-blocker therapy is required, use a cardio-selective beta-blocker. Monitor patients for decreased effects of either agent, such as increased need for/use of beta-2 agonists or increased heart rate or blood pressure.

DISCUSSION: Many patients with asymptomatic or mild reactive airways disease tolerate beta-blockers well. Most patients with COPD do not have bronchospastic component to their illness and may be given beta-blockers. Heart failure treatment guidelines recommend beta-blockers in the presence of COPD. Non-selective beta-blockers have been shown to have a negative effect on lung function (FEV1) and airway hyperresponsiveness (AHR) in patients with asthma and COPD.(1) An open-label study using the nonselective beta blocker nadolol showed no effect on salbutamol in 10 patients with mild asthma not on controller therapy.(2) A study in 8 healthy men showed that long acting propranolol (160 mg) only effected airway dilation at the 200 mcg salbutamol dose. The 800 mcg and 1600 mcg dose were unaffected. However, penbutolol prevented any significant airway dilation with all doses of salbutamol.(3) In a double blind, three-way, crossover study, 44% (7/16 patients) of patients taking metoprolol showed a greater than 20% decrease in FEV1 compared to 19% (3 patients) after dilevalol and 6% (1 patient) after placebo. Dilevalol and metoprolol significantly inhibited isoproterenol response compared to placebo.(4) A double-blind, randomized, crossover study in 10 asthmatic patients showed that intravenous propranolol produced marked symptomatic bronchoconstriction. Only a slight but significant inhibition of bronchomotor sensitivity to isoproterenol was noted during esmolol infusion.(5) In 18 patients with reversible bronchial asthma, labetalol caused a significant increase in FEV1 and metoprolol caused a significant decrease in FEV1. Concurrent administration of isoproterenol and labetalol caused a further increase in FEV1. The effect of isoproterenol was decreased by metoprolol (100, 200mg).(6) In one study propranolol (0.06mg/kg IV) was shown to almost completely block the effects of isoproterenol in asthmatics. Metoprolol (0.12mg/kg IV) did not affect isoproterenol.(7) Studies have shown that cardioselective beta-blockers are safe for patients with asthma and COPD.(8,9,10) Nebivolol and celiprolol significantly decreased FEV1. Inhalation of albuterol (up to 800mcg) significantly improved FEV1, but the values after nebivolol and celiprolol administration were lower than the initial values.(11) Administration of metoprolol did not cause any respiratory problems in 9 asthmatic patients. There was no significant difference between the metoprolol and placebo groups in the respiratory response to an isoproterenol aerosol in 24 asthmatic patients.(12) Eight male asthmatic patients were given 10 mg bisoprolol, 20 mg bisoprolol, and 100 mg metoprolol. Both bisoprolol and metoprolol caused bronchoconstriction measured by a significant fall in PEFR (peak expiratory flow rate). Terbutaline was able to reverse bronchoconstriction in all patients.(13) A double blind, placebo-controlled study analyzed the use of atenolol 100mg, metoprolol 100mg, or acebutolol 400 mg in 8 asthmatic patients before and after exercise. All three drugs reduced significantly FEV1 and PEFR. Administration of terbutaline improved all respiratory indices.(14) A double-blind crossover trial in 10 asthmatic patients showed that a single IV dose of atenolol 3mg caused slight impairment of ventilatory function. A dose of salbutamol by inhalation was able to reverse the bronchial effect of atenolol.(15) Propranolol (80mg/day), oxprenolol (80mg/day), atenolol (100mg/day), and celiprolol 200mg/day were given to 10 asthmatic patients in a randomized, crossover design with a two week washout period between each drug. The non-beta 1 selective beta blockers (propranolol, oxprenolol) caused a significant reduction in FEV1 and inhibited the bronchodilator response to inhaled salbutamol. Atenolol and celiprolol (beta1 selective beta blockers) did not significantly affect respiratory function or antagonize salbutamol effects.(16) A double blind, randomized, within patient, placebo-controlled study compared the cardioselective beta-blocker atenolol to the non-selective propranolol. Atenolol caused a significantly less drop in FEV1 compared to propranolol. The effect of isoprenaline plus the beta blockers were also studied. Both atenolol and propranolol effected isoprenaline FEV1 dose response curves but the greatest displacement was seen with propranolol.(17) The pulmonary effects of celiprolol 200 mg, celiprolol 400mg, propranolol 40mg, atenolol 100 mg were evaluated in 34 asthmatic patients. Propranolol and atenolol caused significant reductions in pulmonary function. Propranolol pretreatment caused a significant reduction in the effect of the bronchodilator. Celiprolol did not antagonize the bronchodilators.(18) A double-blind, placebo controlled, randomized, crossover design study studied the effects of propranolol 80mg or celiprolol 200 or 400mg on pulmonary function. Propranolol produced a significant decrease in FEV1 and FVC. Celiprolol and placebo had similar results. The effect of aerosolized terbutaline was also measured. Even at supratherapeutic doses, terbutaline was unable to restore pulmonary function parameters to baseline levels after treatment with propranolol. Terbutaline caused further bronchodilation after administration of celiprolol.(19) Eleven asthmatic patients showed significant bronchoconstriction in small airways after propranolol 40mg and pindolol 2.5mg in a double blind, randomized trial. Large airways only showed bronchoconstriction with propranolol. Terbutaline 0.5mg subcutaneous was given after pretreatment with propranolol and pindolol. The bronchodilator effect of terbutaline on large airways was diminished after both propranolol and timolol.(20)

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

Beta-Blockers/Anticholinesterases

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Beta-Blockers/Clonidine

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Beta-Blockers/Donepezil; Galantamine

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Beta-Blockers/Moxonidine

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Beta-Blockers/Nsaids; Aspirin (NON-CARDIOPROTECTIVE)

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Beta-Blockers; Diltiazem; Verapamil/Lacosamide

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

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/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 Beta-Blockers/Theophyllines

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

MECHANISM OF ACTION: Certain beta-blockers may inhibit theophylline metabolism. In addition, beta-blockers, especially non-selective agents, can antagonize the pharmacologic effects of theophylline.

CLINICAL EFFECTS: Even though theophylline concentrations may increase leading to increased possibility of theophylline toxicity, beta-blockers decrease theophylline's therapeutic effects.

PREDISPOSING FACTORS: Cigarette smoking may exacerbate this interaction.

PATIENT MANAGEMENT: Avoid the use of non-selective beta-blockers with theophylline. If a beta-blocker must be used, a cardioselective agent that does not decrease the clearance of theophylline (e.g., atenolol) should be considered. However, since cardioselectivity is not absolute and is less selective at higher doses, cardioselective beta-blockers should be used with caution in patients with bronchospastic disease.

DISCUSSION: Inhibition of theophylline metabolism is greatest with lipophilic beta-blockers undergoing hepatic metabolism (e.g., propranolol). Additionally, the decrease in theophylline clearance appears to be dose dependent as the higher the beta-blocker dose, the greater the decrease in theophylline clearance. If the patient is on both drugs and the beta-blocker is discontinued, serum theophylline concentrations may decrease. In these cases, monitor for a decrease in theophylline therapeutic effect and adjust the dose as needed.

Selected Systemic Non-Cardioselective Beta-Blockers/Insulin

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

MECHANISM OF ACTION: Not fully established. Probably blockade of a variety of beta-adrenergic responses to hypoglycemia.

CLINICAL EFFECTS: Diminished response to insulin may occur. Frequency and severity of hypoglycemic episodes may be increased, while warning symptoms of low blood sugar may be masked.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Try to avoid beta-blocker therapy, particularly in diabetics prone to hypoglycemic attacks. One of the cardioselective agents may decrease risk of hypertensive attacks and allow more rapid glucose recovery from hypoglycemia. Patients should be counseled not to rely on tachycardia to diagnose hypoglycemia, since it is masked by beta-blocker therapy. Diaphoresis is unaffected by beta-blockade and can be used by the diabetic to recognize hypoglycemia.

DISCUSSION: A class effect of diminished glucose-lowering effects is expected with concurrent use of beta-blockers and insulin. It is prudent to monitor serum glucose closely in patients receiving beta-blocker therapy because symptoms of hypoglycemia may be masked. A double blind, randomized, 12 month study of 39 patients tested the metabolic effects of pindolol (5 mg BID) compared to control group on insulin sensitivity. The patient's insulin sensitivity index decreased 17% when on pindolol treatment compared to placebo (p<0.01). Insulin mediated glucose uptake was significantly lower (p<0.05) with propranolol treatment than with placebo. (1) A study of 26 patients with chronic heart failure showed that carvedilol (average daily dose 27.5 mg/d) caused a significant decrease in fasting insulin levels (17.09 to 10.77 microU/ml, p <0.05) compared to pre-treatment levels. This trial also showed that patients on carvedilol had significantly (p=0.015) lower fasting insulin levels (10.77 microU/ml) compared to the fasting insulin levels (20.72 microU/ml) of patients on bisoprolol treatment (5.9mg/d).(2)

Slt Non-Cardioselective B-Blockers/Nateglinide; Repaglinide

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

MECHANISM OF ACTION: Not fully established. Probably blockade of a variety of beta-adrenergic responses to hypoglycemia.

CLINICAL EFFECTS: Diminished response to nateglinide and repaglinide may occur. Frequency and severity of hypoglycemic episodes may be increased, while warning symptoms of low blood sugar may be masked.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Try to avoid beta-blocker therapy, particularly in diabetics prone to hypoglycemic attacks. One of the cardioselective agents may decrease risk of hypertensive attacks and allow more rapid glucose recovery from hypoglycemia. Patients should be counseled not to rely on tachycardia to diagnose hypoglycemia, since it is masked by beta-blocker therapy. Diaphoresis is unaffected by beta-blockade and can be used by the diabetic to recognize hypoglycemia.

DISCUSSION: A double blind, randomized, 12 month study of 39 patients tested the metabolic effects of pindolol (5 mg BID) compared to control group on insulin sensitivity. The patient's insulin sensitivity index decreased 17% when on pindolol treatment compared to placebo (p<0.01). Insulin mediated glucose uptake was significantly lower (p<0.05) with propranolol treatment than with placebo. (1) A study of 26 patients with chronic heart failure showed that carvedilol (average daily dose 27.5 mg/d) caused a significant decrease in fasting insulin levels (17.09 to 10.77 microU/ml, p <0.05) compared to pre-treatment levels. This trial also showed that patients on carvedilol had significantly (p=0.015) lower fasting insulin levels (10.77 microU/ml) compared to the fasting insulin levels (20.72 microU/ml) of patients on bisoprolol treatment (5.9mg/d).(2)

Systemic Non-Cardioselective Beta-Blockers/Sulfonylureas

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

MECHANISM OF ACTION: Not fully established. Probably blockade of a variety of beta-adrenergic responses to hypoglycemia.

CLINICAL EFFECTS: Diminished response to sulfonylureas and insulin may occur. Frequency and severity of hypoglycemic episodes may be increased, while warning symptoms of low blood sugar may be masked.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Try to avoid beta-blocker therapy, particularly in diabetics prone to hypoglycemic attacks. One of the cardioselective agents may decrease risk of hypertensive attacks and allow more rapid glucose recovery from hypoglycemia. Patients should be counseled not to rely on tachycardia to diagnose hypoglycemia, since it is masked by beta-blocker therapy. Diaphoresis is unaffected by beta-blockade and can be used by the diabetic to recognize hypoglycemia.

DISCUSSION: A class effect of diminished glucose-lowering effects is expected with concurrent use of beta-blockers and sulfonylureas. It is prudent to monitor serum glucose closely in patients receiving beta-blocker therapy because symptoms of hypoglycemia may be masked. A double blind, randomized, 12 month study of 39 patients tested the metabolic effects of pindolol (5 mg BID) compared to control group on insulin sensitivity. The patient's insulin sensitivity index decreased 17% when on pindolol treatment compared to placebo (p<0.01). Insulin mediated glucose uptake was significantly lower (p<0.05) with propranolol treatment than with placebo.(1) A study of 26 patients with chronic heart failure showed that carvedilol (average daily dose 27.5 mg/d) caused a significant decrease in fasting insulin levels (17.09 to 10.77 microU/ml, p <0.05) compared to pre-treatment levels. This trial also showed that patients on carvedilol had significantly (p=0.015) lower fasting insulin levels (10.77 microU/ml) compared to the fasting insulin levels (20.72 microU/ml) of patients on bisoprolol treatment (5.9mg/d).(2)

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• Acute decompensated heart failure
• Asthma
• Cardiogenic shock
• Complete atrioventricular block
• Incomplete AV heart block
• Right ventricular failure
• Sinus bradycardia

• Chronic obstructive pulmonary disease
• Hypotension
• Pregnancy

• Diabetes mellitus
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Myasthenia gravis
• Raynaud's phenomenon

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Less Frequent

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

Rare or Very Rare

• Acute cognitive impairment
• Arthralgia
• Back pain
• Cardiac arrhythmia
• Chest pain
• Hallucinations
• Leukopenia
• Mesenteric artery thrombosis
• Orthostatic hypotension
• Psoriasiform eruption
• Thrombocytopenic disorder

More Frequent

• Abnormal sexual function
• Drowsy
• Fatigue
• General weakness
• Insomnia

Less Frequent

• Abdominal pain with cramps
• Constipation
• Diarrhea
• Nasal congestion
• Nausea
• Nervousness
• Symptoms of anxiety
• Vomiting

Rare or Very Rare

• Dry eye
• Dysgeusia
• Nightmares
• Ocular irritation
• Pruritus of skin

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Reproduction studies in mice and rabbits using timolol maleate dosages up to 50 times the maximum human dosage have not revealed evidence of harm to the fetus. Although delayed fetal ossification was observed at this dosage in rats, no adverse effects on postnatal development occurred in this species. In pregnant rabbits and mice receiving timolol maleate dosages 100 and 1000 times the maximum human dosage, respectively, an increased incidence of fetal resorption resulted. There are no adequate and controlled studies to date using timolol in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

Timolol is distributed into milk. Because of the potential for serious adverse reactions from timolol in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

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