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Interactions with Propranolol

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Lithium, Nortriptyline, Desipramine, Amitriptyline, Alprazolam, Buspirone, Chlordiazepoxide, Clonazepam, Clorazepate, Diphenhydramine, Doxepin, Fentanyl topical, Fluphenazine, Flurazepam, Hydromorphone (oral), Imipramine, Morphine, Oxycodone, Prochlorperazine, Temazepam, Trazodone, Triazolam, Promethazine (oral), Oxymorphone, Perphenazine, Trimipramine, Amoxapine, Protriptyline, Clomipramine, Mesoridazine, Trifluoperazine, Halazepam, Hydroxyzine, Zolpidem, Estazolam, Quazepam, Carisoprodol, Chlorphenesin, Chlorzoxazone, Cyclobenzaprine, Metaxalone, Methocarbamol, Orphenadrine, Baclofen, Venlafaxine (oral), Methadone, Chloral hydrate, Chloral hydrate rectal, Fentanyl (buccal), Fentanyl citrate (oral transmucosal), Hydromorphone (injection), Hydromorphone (rectal), Meprobamate, Promethazine (rectal), Promethazine (injection), Buprenorphine (oral), Buprenorphine (injection), Mirtazapine, Cabergoline, Butorphanol, Zaleplon, Escitalopram

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

Bupropion (oral)

ADJUST DOSE: Coadministration with bupropion may increase the plasma concentrations of drugs that are metabolized by CYP450 2D6 (e.g., selective serotonin reuptake inhibitors; tricyclic antidepressants; some beta blockers, antiarrhythmics, and antipsychotics). The mechanism is decreased clearance due to inhibition of CYP450 2D6 activity by bupropion. Approximately 93% of Caucasians and more than 98% of Asians and individuals of African descent are extensive metabolizers of CYP450 2D6 and may be affected by this interaction. In a study of 15 male volunteers who were extensive metabolizers of CYP450 2D6, pretreatment with bupropion (150 mg twice daily) increased the peak plasma concentration (Cmax), area under the concentration-time curve (AUC) and half-life of desipramine (50 mg single dose) by an average of 2-, 5-, and 2-fold, respectively. The effect was present for at least 7 days after the last dose of bupropion. In one case report, plasma levels of imipramine and its metabolite, desipramine, increased approximately fourfold in a 64-year-old woman following the addition of bupropion 225 mg/day. Plasma levels of desipramine were increased twofold more than the imipramine levels, which is consistent with the fact that desipramine is primarily metabolized by CYP450 2D6 while imipramine is also metabolized by other CYP450 isoenzymes. Similarly, a 62-year-old woman with no history of seizures developed a generalized tonic-clonic seizure in association with toxic trimipramine plasma levels following the addition of bupropion. No further seizures occurred following dosage reductions of both drugs.

MANAGEMENT: Caution is advised if bupropion must be used concomitantly with medications that undergo metabolism by CYP450 2D6, particularly those with a narrow therapeutic range. Concomitant medications should be initiated at the lower end of the dose range. Clinical and laboratory monitoring may be appropriate for some drugs whenever bupropion is added to or withdrawn from therapy.

Rizatriptan

ADJUST DOSE: Coadministration with propranolol may increase the plasma concentrations of rizatriptan. The exact mechanism is unknown but may involve propranolol inhibition of rizatriptan metabolism via monoamine oxidase, subtype A. In 11 healthy subjects, propranolol (120 mg orally every 12 hours for 7 days) increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of rizatriptan (10 mg single dose) by 75% and 67%, respectively, compared to placebo. A 4-fold increase in rizatriptan AUC was observed in one case. In 20 healthy subjects, reducing the dosage of propranolol (60 mg twice daily for 7 days) and/or staggering the time of administration (1 to 2 hours) lessened somewhat but did not eliminate the effect on rizatriptan pharmacokinetics. In contrast, 25 healthy subjects given a single 10 mg dose of rizatriptan following nadolol (80 mg every 12 hours) or metoprolol (100 mg every 12 hours) for 7 days demonstrated no evidence of a significant pharmacokinetic interaction. No adverse effects were attributed to any of the drug combinations in the studies, and no effect on the active N-monodesmethyl metabolite of rizatriptan was reported.

MANAGEMENT: Caution is advised if rizatriptan must be used with propranolol. Patients treated with propranolol should not receive greater than 5 mg of rizatriptan as a single dose, nor more than a maximum of 3 doses in any 24-hour period. It appears that the full range of rizatriptan dose may be used during coadministration with atenolol, metoprolol, nadolol, or timolol.

Tizanidine

ADJUST DOSE: Tizanidine may potentiate the hypotensive effect of some medications secondary to its alpha-2 adrenergic activity. Pharmacologic studies have found tizanidine to possess between 1/10 to 1/50 of the potency of clonidine, a structurally similar agent, in lowering blood pressure. In a single-dose study where blood pressure was monitored closely after dosing, two-thirds of patients treated with an 8 mg dose had a 20% reduction in either the diastolic or systolic blood pressure. The reduction was seen within 1 hour after dosing, peaked 2 to 3 hours after dosing, and was associated at times with bradycardia, orthostatic hypotension, lightheadedness, dizziness, and rarely, syncope. The hypotensive effect of tizanidine is dose-related and has been measured following single doses of 2 mg or more. In clinical trials, the addition of tizanidine to antihypertensive therapy was associated with a 20% to 30% increase in the incidence of clinically significant decreases in systolic or diastolic blood pressure compared with placebo plus antihypertensive therapy and tizanidine alone. The incidence of orthostatic hypotension was also increased.

MANAGEMENT: Lower initial dosages and cautious dosage titration should be considered when tizanidine is initiated in patients receiving antihypertensive therapy or if antihypertensive therapy is initiated in patients receiving tizanidine. Although single doses of less than 8 mg of tizanidine have not been shown effective for spasticity in controlled clinical studies, it may be prudent to initiate treatment with 4 mg doses and gradually increase in 2 to 4 mg increments until optimum effect is achieved. The dose can be repeated at 6 to 8 hour intervals as needed, up to a maximum of three doses in 24 hours and a total daily dosage of 36 mg. However, experience with single doses exceeding 8 mg and daily doses exceeding 24 mg is limited. Close monitoring for development of hypotension is recommended. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia.

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.

Digoxin (oral)

Because of additive pharmacological effects, bradycardia is more likely when a beta-blocker and digoxin are coadministered than when either drug is used alone. Data are available for propranolol. The patient's heart rate and blood pressure should be measured periodically, especially during the first few weeks of therapy. Patients should be advised to notify their physician if they experience irregular heartbeats, slow pulse, dizziness, or syncope.

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.

Eletriptan

Coadministration with propranolol has been shown to increase the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of eletriptan by 10% and 33%, respectively. The mechanism of interaction is unknown. No interactive increases in blood pressure were observed during the combination, and no dosage adjustment appears 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.

Thioridazine (oral)

CONTRAINDICATED: Coadministration with drugs that are inhibitors of CYP450 2D6 may increase the plasma concentrations of thioridazine and its two active metabolites, mesoridazine and sulforidazine, all of which are substrates of the isoenzyme. Significant increases (up to severalfold) have been observed during coadministration with fluvoxamine, propranolol, and pindolol in pharmacokinetic studies. The use of thioridazine has been associated with dose-related prolongation of the QT interval, thus elevated plasma levels of the drug may potentiate the risk of ventricular arrhythmias such as ventricular tachycardia and torsade de pointes as well as cardiac arrest and sudden death. Several cases of torsade de pointes have been reported.

MANAGEMENT: The use of thioridazine with drugs that inhibit CYP450 2D6 is considered contraindicated. Depending on the elimination half-life of these drugs, a considerable waiting period may be appropriate following their discontinuation before thioridazine is initiated. For example, the manufacturer of fluoxetine recommends that thioridazine not be administered within 5 weeks after discontinuing fluoxetine because of the drug's long half-life.

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.

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.

Sodium oxybate

GENERALLY AVOID: The central nervous system (CNS)- and respiratory-depressant effects of sodium oxybate may be potentiated by other agents with CNS-depressant effects.

MANAGEMENT: Agents with CNS depressant effects should be avoided during sodium oxybate therapy.

Methyldopa

GENERALLY AVOID: The combination of nonselective beta-blockers and methyldopa may cause hypertensive crises. Death has been reported. Causality has not been clearly established, as other drugs were involved. The mechanism may be related to unopposed alpha effects. Phentolamine may be useful for treatment of this interaction.

MANAGEMENT: It may be best to avoid this combination. Patients' blood pressure should be monitored during concurrent therapy. Patients should be advised to seek medical help if they experience any early symptoms of a hypertensive crisis including nausea, vomiting, sweating, flushing, stiff neck, headache, or palpitations.

Theophylline, 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.

Aspirin (oral), Salsalate, Magnesium salicylate, Aspirin (rectal), Diflunisal

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.

Hydralazine

Hydralazine may increase serum levels of some oral beta blockers. The proposed mechanism is reduced hepatic blood flow resulting in decreased biotransformation of beta blockers that undergo extensive first-pass metabolism. The interaction is less likely to occur with sustained-release preparations. Renally excreted beta-blockers such as atenolol, carteolol, nadolol, or sotalol are not expected to interact. This combination generally tends to have beneficial effects and is used commonly in the treatment of hypertension. The patient's clinical response should be monitored.

Chloroquine

In vitro and animal studies have suggested that chloroquine may increase serum levels of some oral beta-blockers. The possible mechanism is inhibition of CYP450 2D6 hepatic metabolism. It is recommended that the patient be monitored for beta-blocker toxicity during coadministration and for beta-blocker efficacy when chloroquine is discontinued. Renally excreted beta-blockers such as atenolol, carteolol, nadolol, or sotalol are not expected to interact.

Ascorbic acid (vitamin C)

Limited data suggest that ascorbic acid may decrease the oral bioavailability of propranolol by possibly interfering with its absorption from the gastrointestinal tract. In 5 healthy subjects, pretreatment with a 2 gram dose of ascorbic acid 30 minutes before an 80 mg dose of propranolol decreased the peak plasma concentration (Cmax) and 24-hour area under the concentration-time curve (AUC) of propranolol by 28% and 37%, respectively, compared to when propranolol was administered alone. The time to reach maximum propranolol concentration (Tmax) was increased from 1.9 to 2.7 hours, and the total amount of drug (including metabolites) recovered in urine was significantly diminished. Although the heart rate decreased less during coadministration with ascorbic acid, the clinical significance is considered minor.

Cholestyramine

Limited data suggest that cholestyramine may decrease the absorption of propranolol, possibly reducing its pharmacologic effect. The clinical significance is unknown and data have been conflicting. Studies with single doses reported decreased propranolol plasma levels but no significant changes in blood pressure or pulse rate. One study found no change in propranolol absorption.

Colestipol

Limited data suggest that colestipol may alter the absorption of propranolol. The clinical significance is unknown. Blood pressure and pulse rate changes were not reported.

Maprotiline

Limited data suggest that propranolol may increase the risk of maprotiline toxicity. The proposed mechanism is decreased hepatic blood flow by propranolol, resulting in reduction of maprotiline metabolism. Patients should be advised to notify their physician if they experience excessive sedation, blurred vision, dry mouth, tremor, or ataxia. The dosage of maprotiline may need to be reduced if an interaction is suspected.

Miglitol

Miglitol may reduce the bioavailability of propranolol by 40%. The mechanism of action and clinical significance of this interaction are unknown. If both drugs must be given together, the patient should be monitored for altered clinical response when either drug is started, stopped or changed in dosage.

Nifedipine, Felodipine, Isradipine, Nicardipine, Bepridil, Amlodipine, Nimodipine, 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.

Furosemide, Bumetanide, Chlorothiazide, Chlorthalidone, Hydrochlorothiazide, Indapamide, Metolazone, 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.

Atropine, Benztropine, Propantheline, Procyclidine, Trihexyphenidyl, Biperiden, Hyoscyamine, Belladonna, Methscopolamine, Clidinium, Glycopyrrolate, Dicyclomine, Oxybutynin (oral), Oxybutynin (transdermal), 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.

Apomorphine

MONITOR: Antihypertensive agents and vasodilators may increase the hypotensive effect of apomorphine due to additive effects. Apomorphine alone has been associated with orthostatic hypotension, hypotension, syncope. and dose dependent decreases in systolic blood pressure. In clinical trials, an increased incidence of myocardial infarction, serious pneumonia, serious falls, and bone and joint injuries were reported in patients receiving concomitant therapy. The cause is unknown, but may be due to increased hypotension.

MANAGEMENT: Caution and close monitoring for altered efficacy and safety are recommended if patients receive apomorphine with an antihypertensive agent or vasodilator. Patients should be made aware of the possible side effects (e.g., dizziness, lightheadedness, orthostasis) and be cautioned about driving, operating machinery, or performing other hazardous tasks, and to arise slowly from a sitting or lying position. They should also be advised to notify their physician if they experience dizziness or fainting.

Modafinil

MONITOR: Based on in vitro inhibition data, coadministration with modafinil may increase the plasma concentrations of drugs that are substrates of the CYP450 2C9 and/or 2C19 isoenzymes. The mechanism is decreased clearance due to inhibition of CYP450 2C9/2C19 activities by modafinil. Pharmacologic response to these drugs may be altered, particularly if they have a narrow therapeutic range. For example, modafinil was implicated in a case of clozapine toxicity, characterized by dizziness, ataxia, and tachycardia. Clozapine serum levels increased from 761 ng/mL to 1400 ng/mL several weeks after concurrent modafinil therapy was initiated.

MANAGEMENT: Patients should be monitored for altered efficacy and safety whenever modafinil is added to or withdrawn from therapy. Dosage adjustments may be required if an interaction is suspected.

Flecainide

MONITOR: Beta-blockers and flecainide may have additive negative inotropic effects. Areas under the curve were increased for both drugs and negative inotropic effects occurred when flecainide and propranolol were given to normal subjects. A case of bradycardia, atrioventricular block and cardiac arrest has been reported after sotalol was added to flecainide; however, causality was not definitely determined.

MANAGEMENT: Careful monitoring of the patient's hemodynamic status is recommended during concomitant administration. 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. Patients should be advised to promptly report symptoms such as dizziness, slow or irregular heartbeats, syncope, or palpitations.

Bupivacaine

MONITOR: Beta-blockers may increase the risk of bupivacaine-induced side effects. The proposed mechanism is increased bupivacaine levels due to hepatic enzyme inhibition (propranolol) and/or additive negative inotropic effects on the heart. Patients with heart failure may be at a greater risk. Data have been conflicting and variable.

MANAGEMENT: Caution is recommended if multiple doses of bupivacaine are administered. Monitoring for drowsiness, mental status changes, convulsions, ECG changes, and hypotension is advisable during concurrent therapy.

Chlorpropamide, Acetohexamide, Glipizide, Glyburide, 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.

Carbamazepine (oral), Valproic acid, Phenytoin (oral), Chlorpheniramine, Ethosuximide, Methsuximide, Metoclopramide, Clemastine, Tripelennamine, Brompheniramine, Cyproheptadine, Azatadine, Phenindamine, Levorphanol, Cyclizine, Meclizine, Dimenhydrinate, Trimethobenzamide, Dronabinol, Molindone, Pimozide (oral), Mephenytoin, Ethotoin, Paramethadione, Trimethadione, Felbamate, Gabapentin, Lamotrigine, Tramadol, Divalproex sodium, Topiramate (oral), Triprolidine, Flavoxate, Carbinoxamine, Pramipexole (oral), Ropinirole (oral), Tiagabine, Sibutramine (oral), Tolcapone, Thalidomide, St. John's wort, Entacapone, Levetiracetam, Oxcarbazepine, Zonisamide, Nabilone, 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.

Indomethacin, Piroxicam

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. Indomethacin and piroxicam have been reported to have greater effects than other NSAIDs and indomethacin effects may be significant in patients with eclampsia.

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.

Sulindac, Tolmetin, Flurbiprofen, Ketorolac, Mefenamic acid, Nabumetone, Etodolac, Oxaprozin, Meclofenamate, 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.

Clonidine, Clonidine transdermal

MONITOR: Clonidine and beta-blockers may have synergistic pharmacodynamic effects resulting in marked AV block, bradycardia and hypotension. Conversely, cases of antagonism of hypotensive effects have been reported, the mechanism of which is unkown. In addition, potentiation of the hypertensive rebound associated with abrupt withdrawal of clonidine or both clonidine and the beta blocker may occur. Increased blood pressure, hypertensive crisis, hypertensive encephalopathy, strokes, and fatalities have been reported after clonidine withdrawal. The proposed mechanism is related to increased catecholamine release after clonidine withdrawal, and concurrent beta-blockade results in unopposed alpha-adrenergic effects of the catecholamines, resulting in vasoconstriction. Patients who discontinue clonidine while taking noncardioselective beta blockers appear to be at a higher risk of developing rebound hypertension.

MANAGEMENT: Close monitoring of blood pressure is recommended for patients receiving this combination. Patients should be advised to notify their physician if they experience a reduced heart rate, dizziness, fainting, or headaches. Clonidine should never be discontinued abruptly, but should be tapered off over 2 to 4 days. The beta blocker should be discontinued a few days before gradually discontinuing the clonidine. It has also been suggested that replacing clonidine and the beta blocker with labetalol (an alpha and beta blocker) may prevent rebound hypertension although some symptoms from increased catecholamine levels occur, or selecting a cardioselective beta blocker (e.g. atenolol, betaxolol, bisoprolol, metoprolol) which is theoretically not expected to exacerbate the pressor response. Patients being withdrawn from clonidine should be carefully monitored for blood pressure changes, severe headache, tremors, apprehension, flushing, nausea, and vomiting.

Diltiazem, Verapamil (oral)

MONITOR CLOSELY: Additive reductions in heart rate, cardiac conduction, and cardiac contractility may occur when calcium channel blockers, especially verapamil and diltiazem, are used concomitantly with beta blockers. 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. Ventricular asystole, sinus arrest, and heart block have also been reported. The risk is increased with high dosages, IV administration, left ventricular dysfunction, or AV conduction abnormalities. Beta blocker ophthalmic solutions may also interact, as they are systemically absorbed and can produce clinically significant systemic effects even at low or undetectable plasma levels. Bradycardia (36 bpm) with wandering atrial pacemaker occurred in a patient taking oral verapamil and timolol ophthalmic drops. 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. Verapamil and diltiazem may also decrease the clearance of some beta blockers.

MANAGEMENT: Close clinical monitoring of patient hemodynamic response and tolerance is recommended if these agents are used together, and the dosage of one or both agents adjusted as necessary. Patients should be advised to promptly report any symptoms including fatigue, headache, fainting, swelling of the extremities, weight gain, shortness of breath, chest pain, increased or decreased heartbeat, or irregular heartbeat.

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.

Mefloquine

MONITOR CLOSELY: Cardiopulmonary arrest has been reported after a single dose of mefloquine in a patient taking propranolol. The mechanism is unknown and causality is unclear. Mefloquine monotherapy or combination therapy with other drugs that affect cardiac conduction may cause ECG changes.

MANAGEMENT: Close clinical monitoring is recommended for patients receiving this combination.

Norepinephrine, 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.

Celecoxib (oral)

MONITOR: Coadministration with celecoxib may increase the plasma concentrations of drugs that are substrates of the CYP450 2D6 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 2D6 activity by celecoxib.

MANAGEMENT: Caution is advised if celecoxib must be used concurrently with medications that undergo metabolism by CYP450 2D6, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever celecoxib is added to or withdrawn from therapy.

Cinacalcet

MONITOR: Coadministration with cinacalcet may increase the plasma concentrations of drugs that are substrates of the CYP450 2D6 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 2D6 activity by cinacalcet, which is expected to occur in patients who are CYP450 2D6 extensive metabolizers (approximately 93% of Caucasians and more than 98% of Asians and individuals of African descent). Concurrent administration of cinacalcet (25 or 100 mg) increased the systemic exposure of amitriptyline (50 mg) and its active metabolite, nortriptyline, by approximately 20% in CYP450 2D6 extensive metabolizers. However, because amitriptyline is metabolized by multiple CYP450 isoenzymes in addition to 2D6, the degree of interaction with cinacalcet may be less than that expected for other drugs that are primarily metabolized by 2D6.

MANAGEMENT: Caution is advised if cinacalcet must be used concurrently with medications that undergo metabolism by CYP450 2D6, particularly those with a narrow therapeutic range (e.g., class IC antiarrhythmic agents, phenothiazines, certain beta blockers, and most tricyclic antidepressants). Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever cinacalcet is added to or withdrawn from therapy.

Darifenacin

MONITOR: Coadministration with darifenacin may increase the plasma concentrations of drugs that are metabolized by CYP450 2D6. The mechanism is decreased clearance due to inhibition of the isoenzyme by darifenacin. According to the product labeling, darifenacin (30 mg once daily) increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of imipramine (a CYP450 2D6 substrate) by 57% and 70%, respectively. These changes were accompanied by a 3.6-fold increase in the mean Cmax and AUC of desipramine, the active metabolite of imipramine. Conversely, some CYP450 2D6 substrates may also increase the plasma concentrations of darifenacin, which is itself metabolized by CYP450 2D6 and may participate in enzymatic competitive inhibition with other substrates.

MANAGEMENT: Caution is advised if darifenacin must be used concomitantly with medications that undergo metabolism by CYP450 2D6, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever darifenacin is added to or withdrawn from therapy. Pharmacologic response to darifenacin should also be monitored more closely whenever a CYP450 2D6 inhibitor is added to or withdrawn from therapy, and the darifenacin dosage adjusted if necessary. Patients should be advised to contact their doctor if they experience undue adverse effects of darifenacin such as severe abdominal pain or constipation for 3 or more days.

Galantamine

MONITOR: Coadministration with drugs that are inhibitors of CYP450 2D6 may increase the plasma concentrations of galantamine, which is primarily metabolized by the isoenzyme. In multiple-dose pharmacokinetic studies, a potent inhibitor such as paroxetine has been shown to increase the area under the plasma concentration-time curve (AUC) of galantamine by 40%. Data from a population pharmacokinetic analysis of 852 patients demonstrated that amitriptyline, fluoxetine, fluvoxamine, and quinidine decreased the clearance of galantamine by about 25% to 33%.

MANAGEMENT: During concomitant therapy with drugs that inhibit CYP450 2D6 activity, the possibility of prolonged and/or increased pharmacologic effects of galantamine should be considered. Patients should be advised to notify their physician if they experience nausea, vomiting, sweating, weakness, salivation, or slower respirations.

Imatinib (oral)

MONITOR: Coadministration with imatinib may increase the plasma concentrations of drugs that are substrates of CYP450 2C9, 2D6 and/or 3A4. The mechanism is decreased clearance due to inhibition of these isoenzymes by imatinib. According to the manufacturer, imatinib increased the mean peak plasma concentration and area under the concentration-time curve of simvastatin (a CYP450 3A4 substrate) by 2- and 3.5-fold, respectively. Data for other substrates are not currently available, although human liver microsome studies indicate that imatinib is a potent competitive inhibitor of all three isoenzymes.

MANAGEMENT: Caution is advised if imatinib must be used concomitantly with medications that undergo metabolism by CYP450 2C9, 2D6 and/or 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever imatinib is added to or withdrawn from therapy.

Ranolazine

MONITOR: Coadministration with ranolazine may increase the plasma concentrations of drugs that are substrates of the CYP450 2D6 isoenzyme. Ranolazine has been shown in vitro to be an inhibitor of CYP450 2D6. However, concomitant use of ranolazine with other drugs that are metabolized by CYP450 2D6 such as tricyclic antidepressants and antipsychotics has not been studied.

MANAGEMENT: Caution is advised if ranolazine must be used concurrently with medications that undergo metabolism by CYP450 2D6, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ranolazine is added to or withdrawn from therapy.

Ritonavir

MONITOR: Coadministration with ritonavir may increase the plasma concentrations of drugs that are substrates of the CYP450 2D6 isoenzyme. The mechanism is decreased clearance due to competitive inhibition of CYP450 2D6 activity by ritonavir. The systemic exposure (AUC) of some coadministered drugs has been reported to increase by up to twofold.

MANAGEMENT: Caution is advised if ritonavir must be used concurrently with medications that undergo metabolism by CYP450 2D6, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ritonavir is added to or withdrawn from therapy.

Terbinafine

MONITOR: Coadministration with terbinafine may increase the plasma concentrations of drugs that are substrates of the CYP450 2D6 isoenzyme. The mechanism is decreased clearance due to inhibition of CYP450 2D6 activity by terbinafine, which is expected to occur in patients who are CYP450 2D6 extensive metabolizers (approximately 93% of Caucasians and more than 98% of Asians and individuals of African descent). A case of nortriptyline (a CYP450 2D6 substrate) intoxication corresponding to significantly increased serum drug concentrations was reported in a patient shortly after the addition of terbinafine. Rechallenge in the patient produced similar results.

MANAGEMENT: Caution is advised if terbinafine must be used concurrently with medications that undergo metabolism by CYP450 2D6, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever terbinafine is added to or withdrawn from therapy. Due to the long elimination half-life of terbinafine, especially following prolonged use, such interactions may be observed for several months after discontinuation of terbinafine therapy.

Voriconazole

MONITOR: Coadministration with voriconazole may increase the plasma concentrations of drugs that are substrates of CYP450 2C19, 2C9, and/or 3A4. The mechanism is decreased clearance due to inhibition of those isoenzymes by voriconazole. Increased plasma levels and/or pharmacologic effects of drugs such as cyclosporine, sirolimus, tacrolimus (3A4 substrates), and warfarin (2C9 substrate) have been reported during coadministration with voriconazole.

MANAGEMENT: Caution is advised if voriconazole must be used concomitantly with medications that undergo metabolism by CYP450 2C19, 2C9 and/or 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever voriconazole is added to or withdrawn from therapy. The manufacturer specifically recommends that a dosage reduction be considered for benzodiazepines, HMG-CoA reductase inhibitors (i.e. statins), and vinca alkaloids that are metabolized by the affected isoenzymes when used with voriconazole.

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.

Prednisolone, Dexamethasone, Hydrocortisone, Methylprednisolone, Prednisone, 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.

Duloxetine

MONITOR: Duloxetine is a moderate inhibitor of CYP450 2D6 and may increase the plasma concentrations of drugs that are substrates of the isoenzyme. According to the product labeling, when duloxetine (60 mg twice a day) was administered in conjunction with a single 50 mg dose of desipramine, a CYP450 2D6 substrate, the systemic exposure (AUC) of desipramine increased 3-fold. Conversely, many CYP450 2D6 substrates can also be competitive or noncompetitive inhibitors of the isoenzyme and may increase the plasma concentrations of duloxetine, which is partially metabolized by CYP450 2D6.

MANAGEMENT: Caution is advised if duloxetine must be used concomitantly with medications that undergo metabolism by CYP450 2D6, particularly those with a narrow therapeutic range such as tricyclic antidepressants, phenothiazines, beta blockers, and class IC antiarrhythmic agents (e.g., propafenone, flecainide). A lower initial dosage, as well as clinical and laboratory monitoring, may be appropriate for some drugs.

Cimetidine

MONITOR: H2 antagonists such as cimetidine increase plasma concentrations of some oral beta-blockers. The mechanism may be related to inhibition of CYP450 metabolism of hepatically metabolized beta-blockers, and/or inhibition of renal tubular secretion of others. The potential inhibition of CYP450 enzymes by other H2 antagonists (ranitidine, famotidine, nizatidine) is significantly less than that of cimetidine and is not expected to be clinically significant.

MANAGEMENT: Clinical monitoring of patient response and tolerance is recommended when cimetidine is added to or discontinued from a beta-blocker regimen.

Fluoxetine, Sertraline, Paroxetine, Fluvoxamine, Citalopram (oral)

MONITOR: Limited clinical data suggest that selective serotonin reuptake inhibitors (SSRIs) may potentiate the pharmacologic effects of some beta-blockers. There have been case reports of patients stabilized on beta-blocker therapy who developed bradycardia, hypotension, and complete heart block following the addition of a SSRI, subsequently requiring discontinuation of one or both agents and/or institution of a permanent pacemaker. The interaction is also corroborated by data from in vitro and clinical studies involving paroxetine and metoprolol conducted by one group of investigators. The proposed mechanism is SSRI inhibition (competitive and/or noncompetitive) of CYP450 2D6, the isoenzyme responsible for the metabolic clearance of beta-blockers such as carvedilol, labetalol, metoprolol, propranolol, and timolol. Paroxetine and norfluoxetine (the active metabolite of fluoxetine), in particular, are potent inhibitors of CYP450 2D6 and may be more likely than other SSRIs to cause the interaction. On the other hand, fluvoxamine is a potent inhibitor of CYP450 1A2 and may significantly interact with propranolol, which is a substrate of both CYP450 2D6 and 1A2.

MANAGEMENT: During concomitant therapy with SSRIs, a lower initial dosage and more cautious titration of the beta-blocker may be appropriate. Cardiac function should be closely monitored and the beta-blocker dosage adjusted accordingly, particularly following initiation, discontinuation or change of dosage of SSRI in patients who are stabilized on their beta-blocker regimen. Due to the long half-life of fluoxetine and its active metabolite, norfluoxetine, the risk of an interaction may exist for an extended period (up to several weeks) after discontinuation of fluoxetine. To avoid the interaction, use of beta-blockers that are primarily eliminated by the kidney (e.g., atenolol, acebutolol, betaxolol, carteolol, nadolol) may be considered.

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.

Clozapine, Risperidone (oral), Olanzapine, Quetiapine, Ziprasidone, Aripiprazole, Paliperidone

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.

Metipranolol ophthalmic, 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.

Propafenone

MONITOR: Propafenone may significantly increase serum levels and effects of some oral beta-blockers. The proposed mechanism is inhibition of CYP450 2D6 first-pass metabolism and decreased hepatic clearance. Data are available for metoprolol and propranolol only; however, other hepatically metabolized oral beta-blockers may also be affected. Renally excreted beta-blockers such as atenolol, carteolol, nadolol, or sotalol are not expected to interact. In addition, negative inotropic effects may be potentiated.

MANAGEMENT: Patients receiving this combination should be monitored for hypotension, heart failure, bradycardia, arrhythmias, and mental status changes. Beta-blocker dosage may be decreased if necessary.

Propoxyphene

MONITOR: Propoxyphene may increase the serum levels of some oral beta-blockers. The proposed mechanism is inhibition of CYP450 2D6 first-pass metabolism and decreased hepatic clearance. Data are available for metoprolol and propranolol only; however, other hepatically metabolized beta-blockers may also be affected. Renally excreted beta-blockers such as atenolol, carteolol, nadolol, or sotalol are not expected to interact.

MANAGEMENT: Patients receiving this combination should be monitored for hypotension, heart failure, bradycardia, arrhythmias, and mental status changes when propoxyphene is added to the patient's medical regimen, and for decreased beta-blockade when propoxyphene is deleted from the regimen. A reduction in beta-blocker dosage may necessary.

Rifampin

MONITOR: Rifampin may decrease serum levels and effects of some oral beta-blockers. The proposed mechanism is increased CYP450 oxidative metabolism of beta-blockers that are hepatically metabolized. Renally excreted beta-blockers such as atenolol, carteolol, nadolol, or sotalol are not expected to interact.

MANAGEMENT: Patients should be monitored for clinical response and tolerance when rifampin is added to or discontinued from a beta-blocker regimen. The beta-blocker dosage may require adjustment.

Bromocriptine, Dihydroergotamine, Ergotamine, 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.

Neostigmine

MONITOR: Severe bradycardia and hypotension may develop during concomitant administration of some beta-blockers and anticholinesterase agents. The mechanism is unknown but may involve additive effects. Data have been conflicting. Some studies have reported no significant changes.

MANAGEMENT: The patient's hemodynamic status should be monitored during coadministration. Patients should be advised to notify their physician if they experience syncope, orthostasis, or a slow pulse.

Octreotide (injectable)

MONITOR: Somatostatin analogs (e.g., octreotide, lanreotide) can decrease heart rate and may potentiate the bradycardic effects of drugs like beta-blockers or calcium channel blockers. Octreotide has commonly been associated with bradycardia (less than 50 bpm), conduction abnormalities, and arrhythmias in acromegalic patients. Occasional cases of sinus bradycardia and ventricular tachycardia have also been reported with lanreotide.

MANAGEMENT: Caution is advised if somatostatin analogs are prescribed with a beta-blocker or calcium channel blocker. Heart rate and blood pressure should be monitored, and the beta-blocker or calcium channel blocker dosage adjusted as necessary.

Chlorpromazine

MONITOR: Some antipsychotic agents and some beta-blockers may mutually inhibit each other's metabolism resulting in increased or additive pharmacologic effects such as hypotension, bradycardia, delirium or seizures. The mechanism may be related to competitive inhibition of CYP450 2D6-mediated first-pass metabolism.

MANAGEMENT: Atenolol, carteolol, or nadolol may be considered as alternatives because they undergo renal elimination and are not expected to interact. If this combination cannot be avoided, decreased dosage of either or both drugs may be necessary and the patient should be closely monitored for cardiovascular or nervous system adverse effects.

Pentobarbital, Phenobarbital, Primidone, Secobarbital, Mephobarbital

MONITOR: Some barbiturates may increase the first-pass metabolism of some orally administered beta-blockers. Decreased bioavailability and decreased beta-blockade may result. Data are available for metoprolol and propranolol only.

MANAGEMENT: Patients should be monitored for adequate clinical response. The beta-blocker dosage may need to be increased. Renally excreted beta-blockers such as atenolol, carteolol, nadolol, or sotalol are not expected to interact.

Disopyramide

MONITOR: Some reports have suggested that some beta-blockers may decrease the clearance of disopyramide and both drugs may have additive cardiac effects. Reduced cardiac output, hypotension and bradycardia are possible. Intravenous administration may increase the risk of adverse effects. In addition, the manufacturer cautions that QT interval prolongation and excessive QRS complex widening may occur with concurrent administration of disopyramide and propranolol. The risk of arrhythmias, including ventricular tachycardia, fibrillation, and torsades de pointes may be increased, especially with IV administration. Significant drug interactions were not reported when oral propranolol and disopyramide were administered to healthy subjects.

MANAGEMENT: Until more information is available, close monitoring of the patient's cardiac output, blood pressure, heart rate, and/or ECG is recommended if these drugs must be used together. Patients should be advised to seek medical help if they experience dizziness, syncope, palpitations, slow or fast pulse, or irregular heartbeats.

Methimazole, Propylthiouracil

MONITOR: The clearance of some beta-blockers with high extraction ratios may be reduced when a euthyroid state is achieved after the addition of antithyroid agents. Sotalol, nadolol, carteolol, and atenolol, which are primarily eliminated by the kidney, do not appear to be affected by changes in thyroid function.

MANAGEMENT: The patient should be closely monitored for altered efficacy and safety while achieving a euthyroid state or when the antithyroid agent dosage is added, discontinued, or changed. Beta blocker dose reductions may be required.

Lithium, Nortriptyline, Desipramine, Amitriptyline, Alprazolam, Buspirone, Chlordiazepoxide, Clonazepam, Clorazepate, Diphenhydramine, Doxepin, Fentanyl topical, Fluphenazine, Flurazepam, Hydromorphone (oral), Imipramine, Morphine, Oxycodone, Prochlorperazine, Temazepam, Trazodone, Triazolam, Promethazine (oral), Oxymorphone, Perphenazine, Trimipramine, Amoxapine, Protriptyline, Clomipramine, Mesoridazine, Trifluoperazine, Halazepam, Hydroxyzine, Zolpidem, Estazolam, Quazepam, Carisoprodol, Chlorphenesin, Chlorzoxazone, Cyclobenzaprine, Metaxalone, Methocarbamol, Orphenadrine, Baclofen, Venlafaxine (oral), Methadone, Chloral hydrate, Chloral hydrate rectal, Fentanyl (buccal), Fentanyl citrate (oral transmucosal), Hydromorphone (injection), Hydromorphone (rectal), Meprobamate, Promethazine (rectal), Promethazine (injection), Buprenorphine (oral), Buprenorphine (injection), Mirtazapine, Cabergoline, Butorphanol, Zaleplon, 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.

Guanabenz, Guanethidine, Prazosin, Reserpine, Terazosin, Guanfacine, Guanadrel, Doxazosin, Alfuzosin

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.

Levodopa

MONITOR: The hypotensive effects of levodopa and antihypertensive agents may be additive. Postural hypotension may occur.

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

Iloprost

MONITOR: Theoretically, iloprost may potentiate the hypotensive effect of vasodilators and antihypertensive agents. Iloprost is a synthetic analogue of prostacyclin PGI2 and can dilate both systemic and pulmonary arterial vascular beds.

MANAGEMENT: Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia. Vital signs and blood pressure should be monitored regularly.

Zileuton

MONITOR: Zileuton is believed to inhibit the hepatic metabolism of propranolol. Propranolol serum concentrations may increase by as much as 100% with a resultant increase in beta blockade.

MANAGEMENT: If zileuton and propranolol must be given concomitantly, the patient should be observed closely for altered propranolol effects and the dose adjusted accordingly. Patients should be advised to notify their physician if they experience syncope,slow pulse, irregular heartbeat, dizziness, or shortness of breath.

Phenelzine, Tranylcypromine, Selegiline (oral), Procarbazine, 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).

Nefazodone

Nefazodone may decrease the area under the plasma concentration-time curve (AUC) of propranolol and its metabolite, 4-hydroxypropranolol. However, reported decreases were small, and the clinical effectiveness of both drugs was unaffected.

Norethindrone, Levonorgestrel, Levonorgestrel emergency contraceptive

Oral contraceptives may decrease the first-pass metabolism of some beta-blockers, resulting in increased serum levels. Monitoring of the patient's clinical response is recommended. Renally excreted beta-blockers such as atenolol, carteolol, nadolol, or sotalol are not expected to interact.

Isoniazid

Propranolol may increase the pharmacologic effects of isoniazid. Data are available for propranolol only. The mechanism and clinical significance are unknown. No special precautions appear to be necessary.

Thiothixene

Propranolol may inhibit the oxidative metabolism of thioxanthenes. The pharmacologic effects of the thioxanthene may be increased. The mechanism may be related to competitive inhibition of CYP450 2D6-mediated first-pass metabolism. The clinical significance of this interaction is unknown. Atenolol, carteolol, nadolol, and sotalol may be considered as alternatives because they undergo renal elimination and are not expected to interact. If this combination cannot be avoided, decreased dosage of either or both drugs may be necessary and the patient should be closely monitored for cardiovascular or nervous system adverse effects.

Procainamide

Some oral beta-blockers may decrease the clearance and increase the serum half-life of procainamide. Increased procainamide half-life and/or serum levels may result. The mechanism and clinical significance of this effect are unknown. Data are available for metoprolol and propranolol only and have been conflicting. If procainamide levels are elevated, reduction either of the beta-blocker dosage or of the procainamide dosage may be considered.

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.

Frovatriptan

The coadministration with propranolol may increase the plasma concentrations of frovatriptan. According to the manufacturer, propranolol increased the peak plasma concentration (Cmax) of frovatriptan (2.5 mg oral dose) by 23% in males and 16% in females. Likewise, the area under the concentration-time curve (AUC) increased by 60% in males and 29% in females. The time to reach peak concentration (Tmax) and half-life were not affected. The mechanism of interaction has not been established. This interaction is unlikely to be of clinical significance.

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.

Oxazepam, Diazepam, Lorazepam, Diazepam rectal

The pharmacologic effects of some benzodiazepines may be increased by some beta-blockers. Propranolol and metoprolol may inhibit the hepatic metabolism of diazepam and other mechanisms may also be involved. Most changes have been clinically insignificant; however, increased reaction times and/or decreased kinetic visual acuity have been reported with some combinations. Observation for altered benzodiazepine effects is recommended if these drugs must be used together. Patients should be warned against driving or operating hazardous machinery.

Levothyroxine, 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.

Acetaminophen (oral/rectal)

Two studies have suggested that propranolol may increase the pharmacologic effects of acetaminophen. The mechanism may be related to inhibition of acetaminophen metabolism. The clinical significance of this interaction is unknown.

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