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Interactions with Sotalol

Contents

If you are currently being treated with any of the following medications, you should not use Sotalol without reading these interactions.

Calcium carbonate, Multivitamins and minerals, Prenatal multivitamins, Calcium acetate, Calcium gluconate, Calcium lactate, Calcium phosphate, tribasic (tricalcium phosphate), Calcium glubionate, Calcium citrate

ADJUST DOSING INTERVAL: Concurrent administration with calcium salts may decrease the oral bioavailability of atenolol and possibly other beta-blockers. The exact mechanism of interaction is unknown. In six healthy subjects, calcium 500 mg (as lactate, carbonate, and gluconate) reduced the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of atenolol (100 mg) by 51% and 32%, respectively. The elimination half-life increased by 44%. Twelve hours after the combination, beta-blocking activity (as indicated by inhibition of exercise tachycardia) was reduced compared to that with atenolol alone. However, during a 4-week treatment in six hypertensive patients, there was no difference in blood pressure values between treatments. The investigators suggest that prolongation of the elimination half-life induced by calcium coadministration may have led to atenolol cumulation during long-term dosing, which compensated for the reduced bioavailability.

MANAGEMENT: It may help to separate the administration times of beta-blockers and calcium products by at least 2 hours. Patients should be monitored for potentially diminished beta-blocking effects following the addition of calcium therapy.

Lanthanum carbonate

ADJUST DOSING INTERVAL: Theoretically, lanthanum carbonate may chelate with certain drugs in the gastrointestinal tract, resulting in reduced oral bioavailability of those drugs during coadministration. However, an in vitro study involving digoxin, enalapril, furosemide, metoprolol, phenytoin, and warfarin found no evidence that lanthanum carbonate forms insoluble complexes with these drugs in simulated gastric fluid. Studies in healthy subjects have also found no effect of lanthanum carbonate (1000 mg for 4 doses) on the absorption of a single dose of digoxin (0.5 mg), metoprolol (100 mg), or warfarin (10 mg).

MANAGEMENT: To minimize the potential for interaction, the product labeling recommends that drugs known to interact with antacids (e.g., ACE inhibitors, beta blockers, bisphosphonates, coumarin derivatives, digitalis glycosides, fluoroquinolones, iron, phenytoin, rifampin, tetracyclines, thyroid preparations, valproic acid) not be taken within 2 hours of administration of lanthanum carbonate.

Zolmitriptan

After one week of dosing with zolmitriptan and propranolol 160 mg/day, the Cmax and AUC of zolmitriptan increased 1.5 times while the Cmax and AUC of the N-desmethyl metabolite decreased by 30% and 15%, respectively. The mechanism of action has not been described. No effects on blood pressure or pulse rate were noted. It does not appear that any special precautions are necessary when coadministering zolmitriptan with beta-blockers, although further post-marketing studies will help to define this interaction.

Tadalafil

Based on their pharmacology, phosphodiesterase-5 (PDE5) inhibitors may conceivably potentiate the hypotensive effect of antihypertensive medications. These agents inhibit PDE5-mediated degradation of cyclic guanosine monophosphate (cGMP), which in vascular smooth muscles can cause peripheral vasodilation. However, clinical pharmacology studies of tadalafil (administered as a 10 mg dose except in studies with angiotensin II receptor (AR) blockers and amlodipine, which used a dose of 20 mg) have demonstrated no clinically significant interaction with various antihypertensive drugs from major classes including calcium channel blockers, ACE inhibitors, beta blockers, thiazide diuretics, and AR blockers. Tadalafil 10 mg and 20 mg also had no clinically significant effect on blood pressure changes due to tamsulosin, an alpha-1a blocker. In addition, analysis of data from Phase 3 clinical trials showed no difference in adverse events in patients taking tadalafil with or without antihypertensive medications. In patients receiving concomitant antihypertensive medications, tadalafil 20 mg may induce a blood pressure decrease that is, in general, minor and not likely to be clinically relevant. Nevertheless, patients should be advised of the potential for interaction and to contact their physician if they experience symptoms of hypotension such as dizziness, lightheadedness, or fainting.

Glucagon

Beta-blockers may blunt the hyperglycemic reaction to glucagon by interfering with beta-adrenergic-mediated hyperglycemic counter-regulatory mechanisms. No special precautions appear to be necessary.

Sucralfate (oral), Aluminum hydroxide, Aluminum carbonate, Magnesium hydroxide, Magnesium oxide

Concurrent administration with aluminum and magnesium antacids has been shown to decrease the oral bioavailability of certain beta-blockers, although data are conflicting. The exact mechanism of interaction is unknown but may involve cation binding of beta-blockers or a reduction in the dissolution rate due to increased gastric pH. In six healthy volunteers, concomitant administration of a single dose of antacid (magnesium hydroxide-aluminum oxide 1200 mg-1800 mg) reduced the peak plasma concentration (Cmax), area under the concentration-time curve (AUC) and 24-hour urinary excretion of sotalol (160 mg) by 27%, 21% and 9%, respectively, while administration of the antacid 2 hours after the sotalol dose produced no change. Pharmacodynamic data suggest that the negative chronotropic effect of sotalol was also reduced up to 4 hours after administration of the combination, although the lack of a placebo control might have confounded the results. In another study, concomitant administration of an aluminum hydroxide antacid in six healthy volunteers decreased atenolol (100 mg) Cmax and AUC by 37% and 33%, respectively. However, the Cmax and AUC of metoprolol (100 mg) in the same group was increased 25% and 11%, respectively, by administration of the antacid. Two other studies with aluminum hydroxide failed to find a significant effect on pharmacokinetics or pharmacodynamics of atenolol and propranolol. Based on available data, the clinical significance of this potential interaction is difficult to determine. As a precaution, patients may want to consider separating the administration times of beta-blockers and antacids or other aluminum- or magnesium-containing products by at least 2 hours.

Cisapride (oral)

CONTRAINDICATED: Cisapride can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction.

MANAGEMENT: The concurrent use of cisapride with other medications that can prolong the QT interval is considered contraindicated.

Dofetilide

CONTRAINDICATED: Dofetilide should not be used with Class I or other Class III antiarrhythmic agents due to the potential for additive effects on myocardial refractoriness. Many of these agents, including dofetilide, can also cause prolongation of the QT interval, thus concomitant use may increase the risk of ventricular arrhythmias such as ventricular tachycardia and torsade de pointes.

MANAGEMENT: Class I (e.g., disopyramide, quinidine, procainamide) and class III (e.g., amiodarone, ibutilide, sotalol) antiarrhythmic agents should be withheld for at least 3 half-lives before administering dofetilide. In the case of amiodarone with its unpredictable pharmacokinetics, dofetilide should not be initiated until serum amiodarone levels are below 0.3 mcg/mL or amiodarone has been withdrawn for at least three months.

Grepafloxacin

CONTRAINDICATED: Grepafloxacin can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction.

MANAGEMENT: The concurrent use of grepafloxacin with other medications that can prolong the QT interval is considered contraindicated.

Halofantrine

CONTRAINDICATED: Halofantrine can cause dose-related prolongation of the QT interval at recommended therapeutic doses. QTc interval prolongation and death have been reported during combination use of halofantrine and mefloquine. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction.

MANAGEMENT: The concurrent use of halofantrine with other medications that can prolong the QT interval is considered contraindicated. Halofantrine should also not be given to patients who have previously taken mefloquine. The manufacturer recommends performing an ECG before initiating halofantrine therapy and monitoring cardiac rhythm during and for 8 to 12 hours after completion of therapy.

Mesoridazine

CONTRAINDICATED: Mesoridazine can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. Mesoridazine overdosage has been associated with ventricular arrhythmias and death.

MANAGEMENT: The concurrent use of mesoridazine with other medications that can prolong the QT interval is considered contraindicated.

Pimozide (oral)

CONTRAINDICATED: Pimozide can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction.

MANAGEMENT: The concurrent use of pimozide with other medications that can prolong the QT interval is considered contraindicated.

Sparfloxacin, Levofloxacin, Moxifloxacin, Gatifloxacin, Gemifloxacin

CONTRAINDICATED: Quinolones such as gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, and sparfloxacin may cause dose-related prolongation of the QT interval in some patients. Coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. Torsade de pointes have been reported in a few patients receiving sparfloxacin alone and with antiarrhythmic agents like amiodarone and disopyramide. There have also been isolated case reports of clinically significant interactions with sotalol, a class III antiarrhythmic agent, for both gatifloxacin and moxifloxacin. Levofloxacin, lomefloxacin, norfloxacin, and ofloxacin alone have been associated with extremely rare cases of torsade de pointes and ventricular tachycardia.

MANAGEMENT: Product labelings for some quinolones recommend avoiding concomitant therapy with class IA (e.g., disopyramide, quinidine, procainamide) and class III (e.g., amiodarone, dofetilide, ibutilide, sotalol) antiarrhythmic agents, as well as bepridil. Sparfloxacin is additionally contraindicated for use with any other medication that can prolong the QT interval such as cisapride, erythromycin, some antipsychotics, and tricyclic antidepressants.

Ranolazine

CONTRAINDICATED: Ranolazine can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. With repeat dosing, the mean effect of ranolazine (1000 mg twice daily) on QTc at Tmax is about 6 msec. However, in 5% of the population, the prolongation of QTc is 15 msec. The relationship between ranolazine plasma level and QTc remains linear over a concentration range up to 4-fold greater than the concentrations produced by a dosage of 1000 mg twice a day, and this relationship is not significantly affected by age, weight, gender, race, heart rate, congestive heart failure NYHA class, or diabetes.

MANAGEMENT: The concurrent use of ranolazine with other medications that can prolong the QT interval is considered contraindicated.

Thioridazine (oral)

CONTRAINDICATED: Thioridazine can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. Thioridazine treatment alone has been associated with several reported cases of torsade de pointes and sudden death.

MANAGEMENT: The concurrent use of thioridazine with other medications that can prolong the QT interval is considered contraindicated.

Ziprasidone

CONTRAINDICATED: Ziprasidone can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction.

MANAGEMENT: The concurrent use of ziprasidone with other medications that can prolong the QT interval is considered contraindicated.

Arsenic trioxide

GENERALLY AVOID: Arsenic trioxide can cause QT interval prolongation and complete atrioventricular block. Theoretically, coadministration with other agents that can prolong the QT interval may increase the risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. During clinical studies involving 40 patients receiving arsenic trioxide for acute promyelocytic leukemia, 16 of them (40%) had at least one ECG tracing with a QTc interval greater than 500 msec. Prolongation of QTc was observed between 1 and 5 weeks after arsenic trioxide infusion and returned towards baseline by the end of 8 weeks. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: If possible, medications that are known to prolong the QT interval should be discontinued prior to initiating therapy with arsenic trioxide and withheld for at least several weeks after completion of therapy. Caution is advised if concomitant use cannot be avoided. Patients should have frequent ECGs and be monitored for arrhythmias when QT intervals are prolonged. An absolute QT interval exceeding 500 msec will require immediate action to correct concomitant risk factors, if any, as well as a thorough assessment of the need for continued therapy. Patients who develop syncope or arrhythmia should be hospitalized for clinical and laboratory monitoring. Arsenic trioxide should be temporarily discontinued until symptoms resolve, the QTc interval regresses to below 460 msec, and electrolyte abnormalities are corrected.

Terfenadine, Astemizole

GENERALLY AVOID: A single case report describes the occurrence of torsades de pointes due to the addition of terfenadine therapy to a patient stable on sotalol. The arrhythmia presented 7 days after terfenadine was started. The mechanism of action is unknown, but is thought to be related to cumulative effects of the drug combination on the QT interval. Other non-sedating antihistamines that can prolong the QT interval may interact similarly.

MANAGEMENT: Alternate antihistamine therapy, such as cetirizine, fexofenadine or loratadine is recommended.

Albuterol inhalation, Metaproterenol, Isoetharine inhalation, Terbutaline inhalation, Bitolterol inhalation, Pirbuterol inhalation, Salmeterol (inhalation), Albuterol, Terbutaline (oral), Levalbuterol, Formoterol, Arformoterol inhalation

GENERALLY AVOID: Beta blockers may antagonize the effects of bronchodilator beta-adrenergic agonists, which may result in life-threatening bronchospasm. The mechanism is increased airway resistance and inhibition of beta-agonist-induced bronchodilation due to beta-2-adrenergic blockade. Ophthalmically applied beta blockers undergo some systemic absorption and may also interact. Propranolol has been used in the treatment of albuterol overdose.

MANAGEMENT: This combination should generally be avoided. If no alternative exists, small doses of a B-1 selective beta-blocker (e.g., acebutolol, atenolol, betaxolol, bisoprolol, or metoprolol) may be preferable; however, extreme caution is advised and patients' respiratory status should be closely monitored. Non-selective beta-blockers are generally considered contraindicated in patients with obstructive airways disease.

Charcoal

GENERALLY AVOID: Charcoal reduces the absorption of sotalol by 99% and effectively shortens its elimination half-life. Subtherapeutic levels will result.

MANAGEMENT: While charcoal is an effective antidote for sotalol overdose, its use as a remedy for GI symptoms should be avoided by patients taking sotalol.

Tamoxifen, Bepridil, Promethazine (oral), Perphenazine, Thiethylperazine, Ondansetron, Trimipramine, Amoxapine, Protriptyline, Clomipramine, Trifluoperazine, Risperidone (oral), Vasopressin, Promethazine (rectal), Promethazine (injection), Ondansetron (injection), Maprotiline, Doxorubicin liposomal, Tizanidine, Daunorubicin liposomal, Epirubicin, Alfuzosin, Palonosetron, Apomorphine, Dasatinib, Vorinostat, Paliperidone, Lapatinib

GENERALLY AVOID: Class IA (e.g., disopyramide, quinidine, procainamide) and class III (e.g., amiodarone, dofetilide, sotalol) antiarrhythmic agents can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: The concurrent use of class IA or class III antiarrhythmic agents with other medications that can prolong the QT interval should preferably be avoided unless benefits are anticipated to outweigh the risks. Caution and clinical monitoring are recommended if these agents are prescribed together, especially to patients with underlying risk factors. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsades de pointes such as dizziness, palpitations, or syncope.

Valsartan

GENERALLY AVOID: In the Valsartan Heart Failure Trial, the combination of valsartan with beta blockers and ACE inhibitors was associated with unfavorable outcomes on morbidity and mortality in heart failure patients. The mechanism is unknown.

MANAGEMENT: The manufacturer recommends that the triple combination of valsartan with a beta blocker and an ACE inhibitor be avoided in heart failure patients.

Isoproterenol inhalation

GENERALLY AVOID: Some beta-blockers may antagonize the bronchodilatory, hypotensive, and tachycardic effects of isoproterenol. The mechanism is blockade of beta-adrenergic receptors, which leads to bronchoconstriction, vasodilation, and increased heart rate. Beta-blockers have been used successfully to treat catecholamine or isoproterenol-induced tachyarrhythmias.

MANAGEMENT: This combination should generally be avoided. Patients who are receiving isoproterenol for cardiac conditions should be closely monitored for adequate therapeutic effect if a beta blocker is added. If no alternative exists, small doses of a B-1 selective beta-blocker (e.g., acebutolol, atenolol, betaxolol, bisoprolol, or metoprolol) may be preferable; however, respiratory status should be closely monitored in patients with obstructive pulmonary disease.

Tacrolimus (oral)

GENERALLY AVOID: Tacrolimus can cause dose-related prolongation of the QT interval. Theoretically, coadministration with class IA (e.g., disopyramide, quinidine, procainamide) or class III (e.g., amiodarone, dofetilide, sotalol) antiarrhythmic agents may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. Pharmacokinetically, some of these agents (e.g., amiodarone, bepridil, disopyramide, dofetilide, quinidine) are also known to be substrates and/or inhibitors of CYP450 3A4 and may inhibit the metabolism of tacrolimus, which could lead to increased blood concentrations and toxicity.

MANAGEMENT: Tacrolimus should probably not be administered with class IA or class III antiarrhythmic agents unless benefits are anticipated to outweigh the risks. Caution and clinical monitoring are recommended if these agents are prescribed together. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope. In addition, tacrolimus blood levels and renal function should be checked frequently when given with known substrates and/or inhibitors of CYP450 3A4, and the dosage adjusted accordingly.

Telithromycin

GENERALLY AVOID: Telithromycin has the potential to prolong the QT interval of the electrocardiogram in some patients. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction.

MANAGEMENT: Telithromycin should be avoided in patients treated with class IA (e.g., disopyramide, quinidine, procainamide) or class III (e.g., amiodarone, dofetilide, sotalol) antiarrhythmic agents.

Oxtriphylline, Aminophylline, Dyphylline

GENERALLY AVOID: The pharmacologic effects of theophyllines and beta-blockers are opposite. Nonselective and high doses of cardioselective beta-blockers may cause severe or fatal bronchospasm by opposing theophylline-induced bronchodilation. Ophthalmic beta-blockers undergo significant systemic absorption and may also interact. In addition, propranolol and other beta-blockers may reduce the CYP450 hepatic metabolism of theophylline, and serum theophylline levels may be increased.

MANAGEMENT: Oral and ophthalmic nonselective beta-blockers (e.g., carteolol, carvedilol, levobunolol, metipranolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, and timolol) are considered contraindicated in patients with bronchospastic diseases. Cardioselective beta-blockers should generally be avoided, or used with extreme caution if no other alternatives are available and the benefits outweigh the risks of potentially severe bronchospasm. If patients do receive this combination, they should be closely monitored for increased serum theophylline levels but decreased bronchodilatory effectiveness.

Abarelix

GENERALLY AVOID: Use of abarelix may cause prolongation of the QT interval in some patients. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. In a single, active-controlled, clinical study comparing abarelix to LHRH (luteinizing hormone releasing hormone) agonist plus nonsteroidal antiandrogen therapy, both therapies were found to prolong the mean Fridericia-corrected QT interval by more than 10 msec from baseline. In approximately 20% of patients in both groups, there were either changes from baseline QTc of greater than 30 msec or end-of-treatment QTc values exceeding 450 msec. Similar results were observed in two other Phase 3 studies with abarelix and the active-control treatments. It is unclear whether these changes were directly related to study drugs, to androgen deprivation therapy, or to other variables.

MANAGEMENT: The concurrent use of abarelix with class IA (e.g., disopyramide, quinidine, procainamide) and class III (e.g., amiodarone, dofetilide, sotalol) antiarrhythmic agents should preferably be avoided unless benefits are anticipated to outweigh the risks.

Vardenafil

GENERALLY AVOID: Vardenafil has been reported to cause prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. In a study of the effect of vardenafil on QT interval in 59 healthy volunteers, therapeutic (10 mg) and supratherapeutic (80 mg) doses of vardenafil produced similar increases in QTc interval as moxifloxacin 400 mg, the active control.

MANAGEMENT: Patients treated with class IA (e.g., disopyramide, quinidine, procainamide) or class III (e.g., amiodarone, dofetilide, ibutilide, sotalol) antiarrhythmic agents, should avoid using vardenafil.

Salsalate, Magnesium salicylate

High doses of salicylates may blunt the antihypertensive effects of beta-blockers. The proposed mechanism is inhibition of prostaglandin synthesis. Low-dose aspirin does not appear to affect blood pressure. In addition, beta-blockers may exert an antiplatelet effect, which may be additive with the effects of some salicylates. Metoprolol may also increase aspirin absorption and/or plasma concentrations of salicylates; however, the clinical significance of this effect is unknown. Data have been conflicting. Until more information is available, patients who require concomitant therapy should be monitored for altered antihypertensive response whenever a salicylate is introduced or discontinued, or when its dosage is modified.

Amlodipine, Nisoldipine (oral)

MONITOR: Additive reductions in heart rate, cardiac conduction, and cardiac contractility may occur when calcium channel blockers are used concomitantly with beta blockers, particularly in patients with ventricular or conduction abnormalities. While this combination may be useful and effective in some situations, potentially serious cardiovascular adverse effects such as congestive heart failure, severe hypotension, and/or exacerbation of angina may occur. The proposed mechanisms include additive slowing in AV conduction, reduced cardiac contractility secondary to beta-blockade, and decreased peripheral vascular resistance secondary to calcium channel blockade. In addition, some calcium channel blockers may inhibit the CYP450 metabolism of hepatically metabolized beta blockers, resulting in increased serum concentrations.

MANAGEMENT: Close clinical monitoring of patient hemodynamic response and tolerance is recommended if a calcium channel blocker is prescribed with a beta blocker, and the dosage of one or both agents adjusted as necessary. The same precaution should be observed when beta blocker ophthalmic solutions are used, since they are systemically absorbed and can produce clinically significant systemic effects even at low or undetectable plasma levels.

Spironolactone, Triamterene, Ethacrynic acid, Torsemide

MONITOR: Although they are often combined in clinical practice, diuretics and beta-blockers may increase the risk of hyperglycemia and hypertriglyceridemia in some patients, especially in patients with diabetes or latent diabetes. In addition, the risk of QT interval prolongation and arrhythmias (e.g. torsades de pointes) due to sotalol may be increased by potassium-depleting diuretics.

MANAGEMENT: Monitoring of serum potassium levels, blood pressure, and blood glucose is recommended during coadministration. Patients should be advised to seek medical assistance if they experience dizziness, weakness, fainting, fast or irregular heartbeats, or loss of blood glucose control.

Procyclidine, Trihexyphenidyl, Biperiden, Hyoscyamine, Belladonna, Methscopolamine, Clidinium, Glycopyrrolate, Dicyclomine, Scopolamine, Scopolamine topical, Tolterodine, Trospium

MONITOR: Anticholinergic agents frequently cause drowsiness and other central nervous system-depressant effects that may be additive with those induced by beta blockers. In addition, these agents may increase heart rate and theoretically may counteract the bradycardic effects of beta blockers. Pharmacokinetically, anticholinergic agents may delay the gastrointestinal absorption of beta blockers and other drugs that are administered orally. The proposed mechanism involves increased gastrointestinal transit time due to reduction of stomach and intestinal motility by anticholinergic agents. In healthy volunteers, pretreatment with propantheline has been shown to prolong the time to reach peak plasma concentration (Tmax) for both atenolol and metoprolol. Propantheline also decreased metoprolol peak plasma concentration (Cmax) but had no effect on its systemic exposure (AUC). In contrast, propantheline increased atenolol AUC but had no effect on its Cmax. The clinical relevance of these changes is probably minimal.

MANAGEMENT: Patients should be monitored for potentially excessive CNS adverse effects (e.g., drowsiness, dizziness, lightheadedness, confusion, blurred vision) if anticholinergic agents are used in combination with beta blockers. Patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them.

Tolazamide, Tolbutamide, Metformin, Glimepiride

MONITOR: Beta-blockers may inhibit hepatic glycogenolysis. Hypoglycemic effects may be increased. Beta-blockers also may blunt and mask the normal physiological response (sweating, tachycardia) to hypoglycemia. In addition, beta-blockers may inhibit insulin secretion and reduce the effect of the oral sulfonylureas in some patients. These effects may be less likely with cardioselective beta-blockers.

MANAGEMENT: In brittle diabetic patients, management consists of closely monitoring blood glucose, particularly during the initial few weeks of coadministration. Patients should be instructed about the need for regular monitoring of blood glucose levels and be aware that certain symptoms of hypoglycemia such as tremors and tachycardia may be masked. However, other symptoms such as headache, dizziness, drowsiness, nausea, hunger, and sweating may be unaffected. The same precautions are applicable in diabetic patients treated with ophthalmic beta blockers.

Repaglinide (oral), Insulin regular, Insulin isophane, Insulin zinc, Insulin zinc extended, Insulin lispro, Insulin glargine, Insulin aspart, Nateglinide (oral), Insulin glulisine, Insulin detemir, Insulin inhalation

MONITOR: Beta blockers may inhibit some of the normal physiological response to hypoglycemia. Symptoms of hypoglycemia such as tremors and tachycardia may be absent, making it more difficult for patients to recognize an oncoming episode. In addition, multiple effects on glucose metabolism have been reported, usually with the non-cardioselective beta blockers (e.g., propranolol, pindolol, timolol) but occasionally also with relatively beta-1 selective agents (e.g., metoprolol). Specifically, inhibition of catecholamine-mediated glycogenolysis and glucose mobilization in association with beta blockade can potentiate insulin-induced hypoglycemia in diabetics and delay the recovery of normal blood glucose levels. Prolonged and severe hypoglycemia may occur, although these events have rarely been reported. Significant increases in blood pressure and bradycardia can also occur during hypoglycemia in diabetics treated with insulin and beta blockers due to antagonism of epinephrine's effect on beta-2 adrenergic receptors, which leads to unopposed alpha adrenergic effects including vasoconstriction. Other effects reported with various beta blockers include decreased glucose tolerance and decreased glucose-induced insulin secretion.

MANAGEMENT: In general, cardioselective beta blockers are considered safer than non-cardioselective agents in the treatment of diabetic patients. Nevertheless, caution is advised if they are prescribed to patients treated with insulin or oral antidiabetic agents that can cause hypoglycemia (e.g., insulin secretagogues), as cardioselectivity is not absolute and larger doses of beta-1 selective agents may pose some of the same risks as nonselective agents. Patients should be instructed about the need for regular monitoring of blood glucose levels and be aware that certain symptoms of hypoglycemia such as tremors and tachycardia may be masked. However, other symptoms such as headache, dizziness, drowsiness, nausea, hunger, and sweating may be unaffected. The same precautions are applicable in diabetic patients treated with ophthalmic beta blockers.

Clemastine, Cyclizine, Meclizine, Dimenhydrinate, Duloxetine, Eszopiclone, Ziconotide, Pregabalin, Rotigotine (transdermal)

MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Cevimeline

MONITOR: Cevimeline may increase the risk of conduction abnormalities when administered with beta-blockers. The decrease in sinus node and AV conduction noted when these agents are used alone theoretically may be enhanced when used concurrently.

MANAGEMENT: Cautious administration of cevimeline with a beta blocker and clinical monitoring of patient response and tolerance are recommended.

Etodolac, Oxaprozin, Meloxicam

MONITOR: Chronic (longer than 1 week) nonsteroidal anti-inflammatory drug (NSAID) administration may attenuate the antihypertensive effects of beta blockers. The proposed mechanism is NSAID-induced inhibition of renal prostaglandin synthesis, which results in unopposed pressor activity producing hypertension.

MANAGEMENT: Patients who require concomitant therapy should be monitored for altered antihypertensive response whenever an NSAID is introduced or discontinued, or when its dosage is modified.

Atazanavir (oral)

MONITOR CLOSELY: Atazanavir has been shown to prolong the PR interval of the electrocardiogram in some patients. Theoretically, coadministration with other agents that prolong the PR interval (e.g., beta blockers, digoxin, verapamil) may result in elevated risk of conduction disturbances and atrioventricular block. In a pharmacokinetic study, no substantial additive effect on the PR interval was observed during coadministration of atazanavir (400 mg once a day) and atenolol (50 mg once a day). However, an additive effect cannot be excluded because data are limited and atazanavir has not been studied in combination with other agents that prolong the PR interval.

MANAGEMENT: Caution is advised if atazanavir is used concomitantly with other agents that prolong the PR interval, particularly those that are metabolized by CYP450 3A4 (e.g., verapamil), since atazanavir is an inhibitor of that isoenzyme.

Dolasetron

MONITOR CLOSELY: Dolasetron can cause dose-related prolongation of the QT interval via its pharmacologically active metabolite, hydrodolasetron. Theoretically, coadministration with other agents that can prolong the QT interval may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. In clinical trials, ECG interval prolongations usually returned to baseline within 6 to 8 hours after administration but lasted more than 24 hours in some patients. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution is recommended when dolasetron is administered concomitantly with drugs that prolong the QT interval (including cumulative high-dose anthracycline therapy), especially to patients with underlying risk factors. ECG monitoring may be appropriate in high-risk patients. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope.

Epinephrine injection

MONITOR CLOSELY: Nonselective beta-blockers increase the pressor response to epinephrine. When these agents are taken together, patients initially may experience severe hypertension, then bradycardia. Stroke has been reported. The mechanism is related to blockade of the beta effects of epinephrine (vasodilation and cardiac stimulation) resulting in more predominant alpha effects (vasoconstriction). If anaphylaxis occurs, beta blockers may attenuate the response to epinephrine. Topically applied epinephrine is not expected to interact.

MANAGEMENT: Extreme caution and close monitoring of blood pressure are indicated if these drugs must be used together. Withdrawal of beta-blockers before the procedure or anesthesia may increase the risk of myocardial ischemia and is not recommended. Selective beta-blockers (i.e., metoprolol, atenolol, acebutolol) may be safer alternatives.

Epoprostenol

MONITOR: Coadministration of epoprostenol may increase the effects of hypotensive agents. While epoprostenol and antihypertensive agents have been used together in many clinical trials, caution is recommended if they must be administered concurrently.

MANAGEMENT: Hemodynamic responses should be monitored during coadministration, especially during the first few weeks of therapy. Patients should be advised to notify their physician if they experience dizziness or syncope.

Cetirizine

MONITOR: Concurrent use of cetirizine or levocetirizine with alcohol or other central nervous system (CNS) depressants may result in additive impairment of mental alertness and performance. Several studies have shown no effect of racemic cetirizine on cognitive function, motor performance, or sleep latency as indicated by objective measurements. However, there have been reports of somnolence, fatigue, and asthenia in some patients treated with cetirizine or levocetirizine in clinical trials.

MANAGEMENT: Concomitant use of cetirizine or levocetirizine with alcohol or other CNS depressants should generally be avoided if possible. In the event that they are used together, patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Cortisone, Triamcinolone (oral and injectable), Triamcinolone inhalation, Betamethasone, Fludrocortisone, Triamcinolone acetonide injection, Budesonide inhalation, Budesonide (oral)

MONITOR: Corticosteroids may antagonize the effects of antihypertensive medications by causing sodium and fluid retention. These effects may be more common with the natural corticosteroids (cortisone, hydrocortisone) which have greater mineralocorticoid activity. In addition, some calcium channel blockers (e.g., diltiazem and verapamil) may increase corticosteroid plasma levels and effects by inhibiting their CYP450 3A4 metabolism.

MANAGEMENT: If concomitant therapy is necessary, it is advisable to monitor the patient's blood pressure, electrolyte levels, weight, and for the development of edema and congestive heart failure. The dosages of antihypertensive medications may require adjustment.

Iopamidol, Ioversol, Iodixanol

MONITOR: Limited data suggest that patients receiving beta blockers may have an increased risk of severe hypotensive and/or hypersensitivity reactions to parenteral iodinated contrast media. In addition, the treatment of allergic/anaphylactoid reactions in these patients may be more difficult. The mechanism is unknown.

MANAGEMENT: Patients who have received beta blockers should be closely monitored for adverse reactions to iodinated contrast media. If anaphylaxis occurs, clinicians should be aware that beta blockers may attenuate the response to epinephrine. Thus, larger doses of epinephrine may be necessary to overcome the bronchospasm, although such large doses can also cause excessive alpha adrenergic stimulation resulting in hypertension, reflex bradycardia, heart block, and possible potentiation of bronchospasm. Alternative treatments recommended include vigorous supportive care (e.g., fluids) and the use of parenteral beta agonists for bronchospasm and norepinephrine for hypotension.

Phenylephrine

MONITOR: Limited evidence suggests that propranolol or other nonselective beta-blockers may lead to an acute hypertensive episode when used in combination with phenylephrine. Beta blockers may enhance the pressor response to phenylephrine by blocking its beta-agonist activity. This may occur with ophthalmic or intravenous , but not intranasal dosage forms of phenylephrine.

MANAGEMENT: The clinician may consider monitoring blood pressure more closely if these drugs are coadministered. The use of cardioselective beta-blockers (e.g., acebutolol, atenolol, metoprolol, bisoprolol, betaxolol) may minimize this interaction.

Midodrine

MONITOR: Midodrine, an alpha-1 adrenergic agent may lead to bradycardia if administered concomitantly with any agent that directly or indirectly reduces heart rate. This may be most important for beta blockers and tricyclic antidepressants.

MANAGEMENT: Patients should be advised to discontinue midodrine if they experience signs or symptoms of decreased heart rate (i.e., slow pulse, dizziness, syncope, cardiac awareness) and to contact their provider for reevaluation.

Olanzapine, Quetiapine, Aripiprazole

MONITOR: Neuroleptic agents may potentiate the hypotensive effect of some medications secondary to their peripheral alpha-1 adrenergic blocking activity. Orthostatic hypotension and syncope associated with vasodilation may occur, particularly during the initial dose titration period of neuroleptic therapy.

MANAGEMENT: Close clinical monitoring for development of hypotension is recommended if neuroleptic agents are prescribed with antihypertensive medications or vasodilators. Patients should be advised to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. A lower starting dosage and slower titration of the neuroleptic agent may be appropriate in patients receiving antihypertensive therapy, especially if they are elderly.

Levobunolol ophthalmic, Timolol ophthalmic, Betaxolol ophthalmic, Carteolol ophthalmic, Levobetaxolol ophthalmic

MONITOR: Ophthalmic beta blocker solutions are systemically absorbed and can produce clinically significant systemic effects even at low or undetectable plasma levels. Additive effects of beta blockade may occur in patients receiving both oral and ophthalmic beta blocking agents.

MANAGEMENT: Blood pressure and intraocular pressure monitoring is recommended during concurrent use. Patients should be advised to notify their physician if they experience a slow pulse, irregular heartbeat, dizziness, shortness of breath, or syncope.

Methysergide, Dihydroergotamine nasal

MONITOR: Several case reports have suggested that beta-blockers may increase the risk of ergot alkaloid-induced arteriospasm. The mechanism is unknown. Peripheral ischemia, hypertension with chest pain, and migraine exacerbation have been reported. Propranolol has been most implicated in this interaction, but other nonselective beta-blockers may behave in a similar fashion. The interaction appears to be rare and patients have taken both drugs without adverse effects.

MANAGEMENT: Except for increased awareness of the interaction, no specific intervention appears to be necessary.

Temazepam, Trazodone, Triazolam, Sertraline, Halazepam, Hydroxyzine, Zolpidem, Estazolam, Quazepam, Carisoprodol, Chlorphenesin, Chlorzoxazone, Cyclobenzaprine, Metaxalone, Methocarbamol, Orphenadrine, Baclofen, Paroxetine, Venlafaxine (oral), Fluvoxamine, Buprenorphine (oral), Buprenorphine (injection), Mirtazapine, Cabergoline, Citalopram (oral), Zaleplon, Sodium oxybate, Escitalopram

MONITOR: The concomitant administration of agents with hypotensive effects and psychotherapeutic agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics), narcotic analgesics, alcohol, or muscle relaxants may additively increase hypotensive and/or central nervous system depressant effects.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for hypotension and excessive or prolonged CNS depression. Ambulatory patients should be made aware of the possibility of additive effects (e.g., drowsiness, dizziness, lightheadedness, confusion, orthostasis, fainting) and be cautioned about driving, operating machinery, or performing other hazardous tasks, and to arise slowly from a sitting or lying position. Patients should also be advised to notify their doctor if they experience excessive side effects that interfere with their normal activities, or dizziness and fainting.

Aldesleukin

MONITOR: The concomitant administration of antihypertensive agents may potentiate the hypotensive effects of aldesleukin. Life-threatening (grade 4) hypotension has been reported with aldesleukin alone.

MANAGEMENT: Blood pressure should be monitored during concomitant administration. Aldesleukin doses should be held if systolic blood pressure falls to less than 90 mmHg.

Pilocarpine

MONITOR: The concomitant use of oral pilocarpine and beta blockers may lead to cardiac conduction disturbances. The mechanism is unknown.

MANAGEMENT: If these drugs must be given together, consider the possibility for arrhythmias and administer with caution. Patients should be advised to notify their physician if they experience irregular or slow heartbeats, palpitations, or syncope.

Tocainide

MONITOR: The concomitant use of tocainide and beta-blockers may have additive effects on cardiac index, left ventricular function, and pulmonary wedge pressure. While significant interactions have not been reported in studies, cases of asystole have been reported in patients with preexisting electrophysiologic abnormalities after tocainide and metoprolol were coadministered. The mechanism is not known, but may be related to an additive effect on the sinus node or conduction system, especially in patients with sick sinus syndrome. Cases of confusion and paranoia have also been reported after coadministration of tocainide and propranolol.

MANAGEMENT: The concomitant use of tocainide and beta blockers should probably be avoided in patients with atrioventricular conduction abnormalities or sick sinus syndrome. This combination should be used cautiously in other patients, with careful dose titration and close clinical and electrocardiographic monitoring for efficacy and safety.

Treprostinil

MONITOR: The concurrent use of treprostinil and agents with hypotensive or vasodilator effects may have additive blood pressure lowering effects. Treprostinil has been used concurrently with diuretics and calcium channel blockers in clinical trials.

MANAGEMENT: If these drugs are used together, it is generally recommended that blood pressure be measured more frequently until a stable blood pressure pattern is observed. Patients should be advised to notify their physician if they experience dizziness or syncope.

Terazosin, Guanfacine, Guanadrel, Doxazosin

MONITOR: The hypotensive effect of beta-blockers and alpha blockers, or adrenergic-neuron-blocking agents, may be additive. Beta-blockers may also blunt reflex tachycardia in response to alpha-blocker-induced hypotension. More severe and more prolonged first-dose effects such as postural hypotension or syncope may result.

MANAGEMENT: Caution is advised if an alpha-adrenergic blocker is added to a patient's beta-blocker regimen. The initial dosage of the alpha-blocker may require reduction. Hemodynamic responses should be monitored during coadministration, especially during the first few weeks of therapy. Patients should be advised to take the alpha-blocker at bedtime and to notify their physician if they experience dizziness or syncope while awake.

Nefazodone

MONITOR: The manufacturer reports that nefazodone may potentiate the hypotensive effects of many drugs. Orthostatic hypotension may occur. The mechanism may be related to additive hypotensive effects. In clinical studies, nefazodone was associated with potentially significant blood pressure decreases (SBP 90 mmHg or less and 20 mmHg or more decrease from baseline) in 5.1% of patients, postural hypotension in 2.8%, and syncope in 0.2% (vs 0.3% for placebo).

MANAGEMENT: The manufacturer recommends caution during concomitant use. Blood pressure monitoring may be advisable. Patients should be advised of the possibility of orthostatic hypotension and to notify their caregiver if they experience symptoms such as lightheadedness, dizziness or syncope.

Phenelzine, Tranylcypromine, Selegiline (oral), Isocarboxazid, Selegiline (transdermal), Linezolid, Rasagiline

Monoamine oxidase inhibitors (MAOIs) may theoretically potentiate the hypotensive effect of some medications. This effect may stem from a gradual MAOI-induced accumulation of false neurotransmitters in peripheral adrenergic neurons that have minimal activity at alpha- and beta-adrenergic receptors, resulting in a functional block of sympathetic neurotransmission. Indeed, MAOIs alone quite commonly produce orthostatic hypotension. In addition, bradycardia has been reported with the concomitant use of beta blockers and MAOIs. The clinical significance of these effects is unknown. If these drugs are coadministered, patients should be monitored for evidence of an interaction (e.g., hypotension, orthostasis, bradycardia, tachycardia, dizziness, or syncope).

Sulfinpyrazone

Sulfinpyrazone may reduce the antihypertensive effect of beta-blockers. The mechanism may be related to induction of beta-blocker metabolism or inhibition of prostaglandin synthesis by sulfinpyrazone. Data are available for oxprenolol only. Close observation for altered beta-blocker effects is recommended if coadministration is necessary.

Apraclonidine ophthalmic

The manufacturer reports that apraclonidine ophthalmic may cause additive or synergistic effects on heart rate and blood pressure if used concomitantly with other medications that affect these parameters, including ophthalmic and systemic beta blockers, cardiac glycosides, and antihypertensive agents. Caution and particular attention to the possibility of more pronounced cardiac effects is recommended when using this combination. Patients should be advised to notify their physician if they experience a slow pulse, irregular heartbeats, dizziness, or syncope.

Brimonidine ophthalmic

The manufacturer reports that brimonidine ophthalmic may cause additive or synergistic effects on heart rate and blood pressure if used concomitantly with other medications that affect these parameters. Caution and particular attention to the possibility of more pronounced cardiac effects is recommended when using this combination. Patients should be advised to notify their physician if they experience a slow pulse, irregular heartbeats, dizziness, or syncope.

Liothyronine, Thyroid (desiccated)

Thyroid hormone therapy may reverse decreased hepatic blood flow associated with hypothyroidism. Increased hepatic metabolism and decreased serum levels of some beta-blockers may result. Data are available for propranolol only. No special precautions are necessary. When hypothyroidism is converted to a euthyroid state, a decrease in beta-blocking effectiveness is possible.

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