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Drug overview for PROPRANOLOL HCL (propranolol hcl):
Generic name: PROPRANOLOL HCL (pro-PRAN-oh-lol)
Drug class: Beta-Blockers (Systemic)
Therapeutic class: Cardiovascular Therapy Agents
Propranolol hydrochloride is a nonselective beta-adrenergic blocking agent (beta-blocker).
Propranolol is used for the management of hypertension, angina, supraventricular and ventricular arrhythmias, acute myocardial infarction (MI), and essential tremor. Propranolol also is used for prophylaxis of migraine headache, management of hypertrophic subaortic stenosis, and as an adjunct in the management of pheochromocytoma. The drug also has been used in the management of thyrotoxicosis+.
The choice of a beta-adrenergic blocking agent (beta-blocker) depends on numerous factors, including pharmacologic properties (e.g., relative beta-selectivity, intrinsic sympathomimetic activity, membrane-stabilizing activity, lipophilicity), pharmacokinetics, intended use, and adverse effect profile, as well as the patient's coexisting disease states or conditions, response, and tolerance. While specific pharmacologic properties and other factors may appropriately influence the choice of a beta-blocker in individual patients, evidence of clinically important differences among the agents in terms of overall efficacy and/or safety is limited. Patients who do not respond to or cannot tolerate one beta-blocker may be successfully treated with a different agent.
In the management of hypertension or chronic stable angina pectoris in patients with chronic obstructive pulmonary disease (COPD) or type 1 diabetes mellitus, many clinicians prefer to use low dosages of a beta1-selective adrenergic blocking agent (e.g., atenolol, metoprolol), rather than a nonselective agent (e.g., nadolol, pindolol, propranolol, timolol). However, selectivity of these agents is relative and dose dependent. Some clinicians also will recommend using a beta1-selective agent or an agent with intrinsic sympathomimetic activity (e.g., pindolol), rather than a nonselective agent, for the management of hypertension or angina pectoris in patients with peripheral vascular disease, but there is no evidence that the choice of beta-blocker substantially affects efficacy.
Nonselective beta-blockers are preferred for the management of hypertension or angina pectoris in patients with coexisting essential tremor or vascular (e.g., migraine) headache. For further information on management and classification of migraine headache, see Vascular Headaches: General Principles in Migraine Therapy, under Uses in Sumatriptan 28:32.28.
Generic name: PROPRANOLOL HCL (pro-PRAN-oh-lol)
Drug class: Beta-Blockers (Systemic)
Therapeutic class: Cardiovascular Therapy Agents
Propranolol hydrochloride is a nonselective beta-adrenergic blocking agent (beta-blocker).
Propranolol is used for the management of hypertension, angina, supraventricular and ventricular arrhythmias, acute myocardial infarction (MI), and essential tremor. Propranolol also is used for prophylaxis of migraine headache, management of hypertrophic subaortic stenosis, and as an adjunct in the management of pheochromocytoma. The drug also has been used in the management of thyrotoxicosis+.
The choice of a beta-adrenergic blocking agent (beta-blocker) depends on numerous factors, including pharmacologic properties (e.g., relative beta-selectivity, intrinsic sympathomimetic activity, membrane-stabilizing activity, lipophilicity), pharmacokinetics, intended use, and adverse effect profile, as well as the patient's coexisting disease states or conditions, response, and tolerance. While specific pharmacologic properties and other factors may appropriately influence the choice of a beta-blocker in individual patients, evidence of clinically important differences among the agents in terms of overall efficacy and/or safety is limited. Patients who do not respond to or cannot tolerate one beta-blocker may be successfully treated with a different agent.
In the management of hypertension or chronic stable angina pectoris in patients with chronic obstructive pulmonary disease (COPD) or type 1 diabetes mellitus, many clinicians prefer to use low dosages of a beta1-selective adrenergic blocking agent (e.g., atenolol, metoprolol), rather than a nonselective agent (e.g., nadolol, pindolol, propranolol, timolol). However, selectivity of these agents is relative and dose dependent. Some clinicians also will recommend using a beta1-selective agent or an agent with intrinsic sympathomimetic activity (e.g., pindolol), rather than a nonselective agent, for the management of hypertension or angina pectoris in patients with peripheral vascular disease, but there is no evidence that the choice of beta-blocker substantially affects efficacy.
Nonselective beta-blockers are preferred for the management of hypertension or angina pectoris in patients with coexisting essential tremor or vascular (e.g., migraine) headache. For further information on management and classification of migraine headache, see Vascular Headaches: General Principles in Migraine Therapy, under Uses in Sumatriptan 28:32.28.
DRUG IMAGES
PROPRANOLOL 20 MG TABLET
PROPRANOLOL 10 MG TABLET
PROPRANOLOL 80 MG TABLET
PROPRANOLOL 40 MG TABLET
PROPRANOLOL 60 MG TABLET
The following indications for PROPRANOLOL HCL (propranolol hcl) have been approved by the FDA:
Indications:
Angina
Essential tremor
Hypertension
Hypertrophic cardiomyopathy
Migraine prevention
Myocardial reinfarction prevention
Pheochromocytoma adjunct therapy
Ventricular rate control in atrial fibrillation
Professional Synonyms:
Adjunct medication therapy for pheochromocytoma
Angina cordis
Angor pectoris
Asymmetrical septal hypertrophy
Benign essential tremor
Elevated blood pressure
Elsner's asthma
Essential hypertension
Familial hypertrophic cardiomyopathy
Heberden's angina
Heberden's asthma
Heberden's disease
Hereditary essential tremor
Hyperpiesia
Hyperpiesis
Hypertensive disorder
Idiopathic hypertrophic subaortic stenosis
Migraine prophylaxis
Myocardial reinfarction prophylaxis
Rougnon-Heberden disease
Stenocardia
Systemic arterial hypertension
Indications:
Angina
Essential tremor
Hypertension
Hypertrophic cardiomyopathy
Migraine prevention
Myocardial reinfarction prevention
Pheochromocytoma adjunct therapy
Ventricular rate control in atrial fibrillation
Professional Synonyms:
Adjunct medication therapy for pheochromocytoma
Angina cordis
Angor pectoris
Asymmetrical septal hypertrophy
Benign essential tremor
Elevated blood pressure
Elsner's asthma
Essential hypertension
Familial hypertrophic cardiomyopathy
Heberden's angina
Heberden's asthma
Heberden's disease
Hereditary essential tremor
Hyperpiesia
Hyperpiesis
Hypertensive disorder
Idiopathic hypertrophic subaortic stenosis
Migraine prophylaxis
Myocardial reinfarction prophylaxis
Rougnon-Heberden disease
Stenocardia
Systemic arterial hypertension
The following dosing information is available for PROPRANOLOL HCL (propranolol hcl):
Since there is no consistent interpatient correlation between the dosage of propranolol hydrochloride and therapeutic response, especially after oral administration, dosage must be carefully individualized according to the response of the patient. If patients are switched from the conventional tablets to the extended-release capsules, care should be taken to ensure that the desired therapeutic effect is maintained. The extended-release capsules should not be considered a simple substitute for the conventional tablets on a mg-for-mg basis, since the capsules produce lower blood concentrations.
If patients are switched to the extended-release capsules, the need for dosage retitration should be considered, especially to maintain effectiveness at the end of the dosing interval.
The manufacturers of propranolol hydrochloride injection state that a reduction in the dosage of propranolol hydrochloride may be necessary in geriatric patients.
The manufacturers of propranolol hydrochloride injection state that a reduction in the dosage of propranolol hydrochloride may be necessary in patients with hepatic impairment.
If patients are switched to the extended-release capsules, the need for dosage retitration should be considered, especially to maintain effectiveness at the end of the dosing interval.
The manufacturers of propranolol hydrochloride injection state that a reduction in the dosage of propranolol hydrochloride may be necessary in geriatric patients.
The manufacturers of propranolol hydrochloride injection state that a reduction in the dosage of propranolol hydrochloride may be necessary in patients with hepatic impairment.
Propranolol hydrochloride is usually administered orally. When administered orally in divided doses, the drug should be given before meals and at bedtime. When propranolol hydrochloride extended-release capsules are administered, the entire daily dose is given once daily.
When propranolol hydrochloride oral concentrate solution is used, the dose should be diluted (e.g., with water, juice, carbonated beverages) or mixed with semisolid foods (e.g., applesauce, puddings) just prior to administration. For the treatment of cardiac arrhythmias, propranolol has been given IV. Oral therapy should replace IV therapy as soon as possible.
When propranolol hydrochloride oral concentrate solution is used, the dose should be diluted (e.g., with water, juice, carbonated beverages) or mixed with semisolid foods (e.g., applesauce, puddings) just prior to administration. For the treatment of cardiac arrhythmias, propranolol has been given IV. Oral therapy should replace IV therapy as soon as possible.
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| PROPRANOLOL 10 MG TABLET | Maintenance | Adults take 2 tablets (20 mg) by oral route 3 times per day |
| PROPRANOLOL 20 MG TABLET | Maintenance | Adults take 1 tablet (20 mg) by oral route 3 times per day |
| PROPRANOLOL 40 MG TABLET | Maintenance | Adults take 1 tablet (40 mg) by oral route 2 times per day |
| PROPRANOLOL 80 MG TABLET | Maintenance | Adults take 1 tablet (80 mg) by oral route 2 times per day |
| PROPRANOLOL 60 MG TABLET | Maintenance | Adults take 1 tablet (60 mg) by oral route 2 times per day |
| DRUG LABEL | DOSING TYPE | DOSING INSTRUCTIONS |
|---|---|---|
| PROPRANOLOL 10 MG TABLET | Maintenance | Adults take 2 tablets (20 mg) by oral route 3 times per day |
| PROPRANOLOL 20 MG TABLET | Maintenance | Adults take 1 tablet (20 mg) by oral route 3 times per day |
| PROPRANOLOL 40 MG TABLET | Maintenance | Adults take 1 tablet (40 mg) by oral route 2 times per day |
| PROPRANOLOL 80 MG TABLET | Maintenance | Adults take 1 tablet (80 mg) by oral route 2 times per day |
| PROPRANOLOL 60 MG TABLET | Maintenance | Adults take 1 tablet (60 mg) by oral route 2 times per day |
The following drug interaction information is available for PROPRANOLOL HCL (propranolol hcl):
There are 3 contraindications.
These drug combinations generally should not be dispensed or administered to the same patient. A manufacturer label warning that indicates the contraindication warrants inclusion of a drug combination in this category, regardless of clinical evidence or lack of clinical evidence to support the contraindication.
| Drug Interaction | Drug Names |
|---|---|
| Thioridazine/Pindolol; Propranolol SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Pindolol and propranolol may inhibit the metabolism of thioridazine at CYP3A4.(1) CLINICAL EFFECTS: Concurrent use of pindolol or propranolol with thioridazine may result in elevated levels of thioridazine and prolongation of the QTc interval, which may result in potentially life-threatening arrhythmias,(1) and elevated levels of the beta blocker. PREDISPOSING FACTORS: The risk of QT prolongation or torsades de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsades de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(4) Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentration of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(4) PATIENT MANAGEMENT: The manufacturer of thioridazine states that concurrent use with pindolol or propranolol is contraindicated.(1) If concurrent therapy is deemed medically necessary, consider obtaining serum calcium, magnesium, and potassium levels and monitoring ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: In one study, two patients receiving thioridazine (600 mg/day to 800 mg/day) developed thioridazine levels that were in the potentially toxic range following the administration of propranolol. In one patient, thioridazine levels increased 433% over 40 days of concurrent therapy. The other patient's level increased 275% after 26 days of concurrent therapy. Neither patient exhibited any signs or symptoms of thioridazine toxicity.(2) In another study, administration of pindolol (40 mg/day) to eight patients receiving thioridazine (150 mg/day) resulted in an increase in thioridazine levels by 36%, as well as increases in the levels of the thioridazine metabolites. In addition, in seven patients, pindolol levels were found to be increased when administered with thioridazine.(3) |
THIORIDAZINE HCL, THIORIDAZINE HYDROCHLORIDE |
| Disopyramide/Class IB, II, and IV Antiarrhythmics SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Disopyramide has been shown to prolong the QTc interval. Concurrent use with other agents that affect the heart rate and rhythm may result in unpredictable effect on heart rhythm.(1-2) CLINICAL EFFECTS: The concurrent use of disopyramide with other agents that affect the heart rate and rhythm may result in in potentially life-threatening cardiac arrhythmias, including torsades de pointes.(1-2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The US manufacturer of disopyramide states that concurrent use of disopyramide with antiarrhythmic agents should be reserved for patients with life-threatening arrhythmias who are demonstrably unresponsive to single-agent antiarrhythmic therapy. The Australian manufacturer of disopyramide states that the concurrent use of other antiarrhythmics, such as Class I, II, III, or IV is contraindicated.(1) The US manufacturer of verapamil states that disopyramide should not be administered within 48 hours before or 24 hours after verapamil.(2) If concurrent therapy is deemed medically necessary, obtain serum calcium, magnesium, and potassium levels and monitor ECG at baseline and at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. DISCUSSION: Because combinations of antiarrhythmics are not well researched and concurrent use may result in unpredictable effects, the Australian manufacturer of disopyramide states that the concurrent use of other antiarrhythmics, such as Class I, II, III, or IV is contraindicated.(1) |
DISOPYRAMIDE PHOSPHATE, NORPACE, NORPACE CR |
| Fezolinetant/CYP1A2 Inhibitors SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient. MECHANISM OF ACTION: Inhibitors of CYP1A2 may inhibit the metabolism of fezolinetant.(1-4) CLINICAL EFFECTS: Concurrent use of a CYP1A2 inhibitor may increase levels of and adverse effects from fezolinetant.(1-4) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Recommendations for concurrent use of fezolinetant with CYP1A2 inhibitors differ in different regions. The US manufacturer of fezolinetant states that concurrent use with strong, moderate, and weak CYP1A2 inhibitors is contraindicated.(1) The Australian, Canadian, and UK manufacturers of fezolinetant state that concurrent use with strong and moderate CYP1A2 inhibitors is contraindicated, while weak CYP1A2 inhibitors are not predicted to cause clinically relevant changes in fezolinetant exposure.(2-4) DISCUSSION: In a study, fluvoxamine, a strong CYP1A2 inhibitor, increased fezolinetant maximum concentration (Cmax) and area-under-curve (AUC) by 80% and 840%, respectively. Mexiletine (400 mg every 8 hours), a moderate CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 40% and 360%, respectively. Cimetidine (300 mg every 6 hours), a weak CYP1A2 inhibitor, increased fezolinetant Cmax and AUC by 30% and 100%, respectively.(1) Strong CYP1A2 inhibitors linked to this monograph include angelica root, ciprofloxacin, enasidenib, enoxacin, fluvoxamine, and rofecoxib. Moderate CYP1A2 inhibitors linked to this monograph include capmatinib, dipyrone, fexinidazole, genistein, hormonal contraceptives, methoxsalen, mexiletine, osilodrostat, phenylpropanolamine, pipemidic acid, rucaparib, troleandomycin, vemurafenib, and viloxazine. Weak CYP1A2 inhibitors linked to this monograph include allopurinol, artemisinin, caffeine, cannabidiol, cimetidine, curcumin, dan-shen, deferasirox, disulfiram, Echinacea, famotidine, ginseng, norfloxacin, obeticholic acid, parsley, piperine, propafenone, propranolol, ribociclib, simeprevir, thiabendazole, ticlopidine, triclabendazole, verapamil, zileuton.(5-7) |
VEOZAH |
There are 12 severe interactions.
These drug interactions can produce serious consequences in most patients. Actions required for severe interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration scheduling, and providing additional patient monitoring. Review the full interaction monograph for more information.
| Drug Interaction | Drug Names |
|---|---|
| Epinephrine/Non-Cardioselective Beta-Blockers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Concurrent use of beta-blockers also block the beta effects of epinephrine, which results in predomination of alpha effects. The plasma clearance of epinephrine is decreased. CLINICAL EFFECTS: Concurrent use of epinephrine with beta-blockers may result in hypertension with reflex bradycardia. Epinephrine resistance in patients with anaphylaxis has been reported. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Avoid concomitant administration of epinephrine and beta-blockers if possible. If both drugs are administered, monitor blood pressure carefully. Hypertension and bradycardia are less likely to occur with cardioselective beta-blockers. Use caution when treating anaphylaxis with epinephrine since response may be poor. DISCUSSION: In a study of 6 subjects, an increase in mean arterial pressure (MAP) of 15.1% (p < 0.05) was observed after an infusion of epinephrine (10 ng/kg/min) followed by an intravenous injection of propranolol (40 mcg/kg). In addition, plasma clearance of epinephrine decreased to 54.7% of the control value after the dose of propranolol.(1) In another study of 6 subjects, patients were intravenously administered 15 mcg epinephrine, followed by propranolol 0.04 mg/kg, and then another dose of epinephrine. A mean decrease in heart rate of 37% (p < 0.001) was observed following the second dose of epinephrine.(2) In a study in 10 healthy subjects, an increase in MAP was observed after infusion of epinephrine (5 mcg/min) followed by infusion of propranolol (10 mg).(5) In a study in 1 healthy subject, marked bradycardia and atrioventricular block occurred after administration of propranolol (40 mg orally) with epinephrine (17 mcg/min intravenously).(6) In a study in 7 healthy subjects, and increase in MAP (8% increase in systolic blood pressure, 10% increase in diastolic blood pressure) was observed after injection of epinephrine (45 mcg in lidocaine) in to the maxilla after pretreatment with pindolol (5 mg).(7) A retrospective analysis of sinus surgery patients found that 9.1% had exaggerated intraoperative hypertensive events during the first surgical hour (defined as relative increase greater than 20% of systolic blood pressure or single systolic blood pressure value above 200 mmHg). Subjects with established beta blockade were found to be three times as likely to experience an exaggerated hypertensive event during the first intraoperative hour.(8) In a study, intraoral injection with 2% lidocaine containing epinephrine (45 mcg) after pretreatment with pindolol (5 mg) resulted reduced stroke volume, increase in afterload, decreased myocardial contractility, decreased heart rate, and an increase in blood pressure.(9) In a study in 8 subjects, a comparison of propranolol (80 mg three times daily) or metoprolol (100 mg three times daily) with epinephrine (8 mcg/min for 6 minutes) showed that propranolol significantly increases MAP while metoprolol, a beta1-selective beta-blocker, does not.(10) There are several case reports of significant hypertension with reflex bradycardia.(9-12) In some of these case reports patients had strokes.(12) |
ADRENALIN, ARTICADENT DENTAL, ARTICAINE-EPINEPHRINE, ARTICAINE-EPINEPHRINE BIT, BUFFERED LIDOCAINE-EPINEPHRINE, BUPIVACAINE HCL-EPINEPHRINE, BUPIVACAINE-DEXAMETH-EPINEPHRN, CITANEST FORTE DENTAL, EPINEPHRINE, EPINEPHRINE BITARTRATE, EPINEPHRINE HCL-0.9% NACL, EPINEPHRINE HCL-D5W, EPINEPHRINE-0.9% NACL, EPINEPHRINE-D5W, LIDOCAINE HCL-EPINEPHRINE, LIDOCAINE HCL-EPINEPHRINE-NACL, LIDOCAINE-EPINEPHRINE, LIGNOSPAN STANDARD, MARCAINE-EPINEPHRINE, ORABLOC, R.E.C.K.(ROPIV-EPI-CLON-KETOR), RACEPINEPHRINE HCL, SENSORCAINE-EPINEPHRINE, SENSORCAINE-MPF EPINEPHRINE, SEPTOCAINE, VIVACAINE, XYLOCAINE DENTAL-EPINEPHRINE, XYLOCAINE WITH EPINEPHRINE, XYLOCAINE-MPF WITH EPINEPHRINE |
| Methyldopa/Beta-Blockers (Nonselective) SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Unopposed alpha-adrenergic vasoconstriction produced by alpha-methylnorepinephrine in the presence of beta-blockade. CLINICAL EFFECTS: Severe hypertension. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor blood pressure during concomitant administration of methyldopa and a nonselective beta-blocker. If hypertension occurs, treatment with phentolamine should be considered. DISCUSSION: Although methyldopa and propranolol have been used together to treat hypertension, severe increases in blood pressure, including death in one patient, has been reported during administration of these drugs. In addition, methyldopa alone has been reported to cause paradoxical hypertension. Additional studies are needed to define the specific population at risk. |
METHYLDOPA, METHYLDOPA-HYDROCHLOROTHIAZIDE, METHYLDOPATE HCL |
| Fingolimod/Beta-Blockers; AV Node Blockers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Initiation of fingolimod has a negative chronotropic effect leading to a mean decrease in heart rate of 13 beats per minute (bpm) after the first dose. The first dose has also been associated with heart block. Beta-blockers or agents which slow AV node conduction further increase the risk for symptomatic bradycardia or heart block. CLINICAL EFFECTS: The heart rate lowering effect of fingolimod is biphasic with an initial decrease usually within 6 hours, followed by a second decrease 12 to 24 hours after the first dose. Symptomatic bradycardia and heart block have been observed. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes. The cause of death in a patient who died within 24 hour after taking the first dose of fingolimod was not conclusive; however a link to fingolimod or a drug interaction with fingolimod could not be ruled out. Beta-Blockers linked to this monograph are: atenolol, betaxolol, bisoprolol, carvedilol, esmolol, landiolol, labetalol, metoprolol, nadolol, nebivolol, propranolol and timolol. AV Node Blocking agents are:digoxin, diltiazem, flecainide, ivabradine, propafenone and verapamil. PREDISPOSING FACTORS: Pre-existing cardiovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, history of torsades de pointes, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to fingolimod initiation, or factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia, bradycardia, female gender, or advanced age) may increase risk for cardiovascular toxicity due to fingolimod. Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(5) PATIENT MANAGEMENT: Fingolimod is contraindicated in patients with Class III/IV heart failure or in patients who have experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA) or decompensated heart failure within the past six months.(1) Patients with pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, or heart block), severe untreated sleep apnea, or a prolonged QTc interval prior to fingolimod initiation should receive cardiologist consultation to evaluate the risks of fingolimod therapy. Patients receiving agents linked to this monograph should have their physician evaluate the possibility of a switch to agents which do not slow heart rate or cardiac conduction. If fingolimod is initiated, the patient should stay overnight in a medical facility with continuous ECG monitoring after the first dose. Correct hypokalemia or hypomagnesemia prior to starting fingolimod. US monitoring recommendations in addition to continuous ECG with overnight monitoring: Check blood pressure hourly. If heart rate (HR) is < 45 beats per minute (BPM) or if the ECG shows new onset of second degree or higher AV block at the end of the monitoring period, then monitoring should continue until the finding has resolved. If patient requires treatment for symptomatic bradycardia, the first dose monitoring strategy should be repeated for the second dose of fingolimod. If, within the first two weeks of treatment one or more fingolimod doses is missed, then first dose procedures are recommended upon resumption. If during weeks 3 and 4 of fingolimod treatment dose is interrupted more than 7 days, then first dose procedures are recommended upon resumption. United Kingdom recommendations(3): Obtain a 12-lead ECG prior to initiating fingolimod therapy. Consult a cardiologist for pretreatment risk-benefit assessment if patient has a resting heart rate less than 55 bpm, history of syncope, second degree or greater AV block, sick-sinus syndrome, concurrent therapy with beta-blockers, Class Ia, or Class III antiarrhythmics, heart failure or other significant cardiovascular disease. Perform continuous ECG monitoring, measure blood pressure and heart rate every hour, and perform a 12-lead ECG 6 hours after the first dose. Monitoring should be extended beyond 6 hours if symptomatic bradycardia or new onset of second degree AV block, Mobitz Type II or third degree AV block has occurred at any time during the monitoring period. If heart rate 6 hours after the first dose is less than 40 bpm, has decreased more than 20 bpm compared with baseline, or if a new onset second degree AV block, Mobitz Type I (Wenckebach) persists, then monitoring should also be continued. If fingolimod treatment is discontinued for more than two weeks, the effects on heart rate and conduction could recur. Thus, first dose monitoring precautions should be followed upon reintroduction of fingolimod. DISCUSSION: After the first dose of fingolimod, heart rate decrease may begin within an hour. Decline is usually maximal at approximately 6 hours followed by a second decrease 12 to 24 hours after the first dose. The second dose may further decrease heart rate, but the magnitude of change is smaller than the first dose. With continued, chronic dosing, heart rate gradually returns to baseline in about one month.(1,2) Diurnal variation in heart rate and response to exercise are not affected by fingolimod treatment.(2) In a manufacturer sponsored study, fingolimod and atenolol 50 mg daily lowered heart rate 15% more than fingolimod alone. However, additional heart rate lowering was not seen with the combination of extended release diltiazem and fingolimod compared with fingolimod alone.(1) |
FINGOLIMOD, GILENYA, TASCENSO ODT |
| Beta-2 Agonists/Non-Cardioselective Beta-Blockers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Non-cardioselective beta-blockers and beta-2 agonists may antagonize the effects of each other. CLINICAL EFFECTS: Diminished response to either the beta-agonist, beta-blocker, or both may occur. Beta-blockers may also induce bronchospasm. PREDISPOSING FACTORS: Patients receiving beta-2 agonists for the treatment of asthma may be more at risk for bronchospasm. PATIENT MANAGEMENT: If possible, avoid beta-blocker therapy in asthmatic patients requiring beta-2 agonist therapy. If beta-blocker therapy is required, use a cardio-selective beta-blocker. For timolol ophthalmic drops, counsel patients to apply pressure to the inner corner of the eye after administration to prevent systemic absorption. Monitor patients for decreased effects of either agent, such as increased need for/use of beta-2 agonists or increased heart rate or blood pressure. DISCUSSION: Many patients with asymptomatic or mild reactive airways disease tolerate beta-blockers well. Most patients with COPD do not have bronchospastic component to their illness and may be given beta-blockers. Heart failure treatment guidelines recommend beta-blockers in the presence of COPD. Non-selective beta-blockers have been shown to have a negative effect on lung function (FEV1) and airway hyperresponsiveness (AHR) in patients with asthma and COPD.(1) An open-label study using the nonselective beta blocker nadolol showed no effect on salbutamol in 10 patients with mild asthma not on controller therapy.(2) A study in 8 healthy men showed that long acting propranolol (160 mg) only effected airway dilation at the 200 mcg salbutamol dose. The 800 mcg and 1600 mcg dose were unaffected. However, penbutolol prevented any significant airway dilation with all doses of salbutamol.(3) In a double blind, three-way, crossover study, 44% (7/16 patients) of patients taking metoprolol showed a greater than 20% decrease in FEV1 compared to 19% (3 patients) after dilevalol and 6% (1 patient) after placebo. Dilevalol and metoprolol significantly inhibited isoproterenol response compared to placebo.(4) A double-blind, randomized, crossover study in 10 asthmatic patients showed that intravenous propranolol produced marked symptomatic bronchoconstriction. Only a slight but significant inhibition of bronchomotor sensitivity to isoproterenol was noted during esmolol infusion.(5) In 18 patients with reversible bronchial asthma, labetalol caused a significant increase in FEV1 and metoprolol caused a significant decrease in FEV1. Concurrent administration of isoproterenol and labetalol caused a further increase in FEV1. The effect of isoproterenol was decreased by metoprolol (100, 200mg).(6) In one study propranolol (0.06mg/kg IV) was shown to almost completely block the effects of isoproterenol in asthmatics. Metoprolol (0.12mg/kg IV) did not affect isoproterenol.(7) Studies have shown that cardioselective beta-blockers are safe for patients with asthma and COPD.(8,9,10) Nebivolol and celiprolol significantly decreased FEV1. Inhalation of albuterol (up to 800mcg) significantly improved FEV1, but the values after nebivolol and celiprolol administration were lower than the initial values.(11) Administration of metoprolol did not cause any respiratory problems in 9 asthmatic patients. There was no significant difference between the metoprolol and placebo groups in the respiratory response to an isoproterenol aerosol in 24 asthmatic patients.(12) Eight male asthmatic patients were given 10 mg bisoprolol, 20 mg bisoprolol, and 100 mg metoprolol. Both bisoprolol and metoprolol caused bronchoconstriction measured by a significant fall in PEFR (peak expiratory flow rate). Terbutaline was able to reverse bronchoconstriction in all patients.(13) A double blind, placebo-controlled study analyzed the use of atenolol 100mg, metoprolol 100mg, or acebutolol 400 mg in 8 asthmatic patients before and after exercise. All three drugs reduced significantly FEV1 and PEFR. Administration of terbutaline improved all respiratory indices.(14) A double-blind crossover trial in 10 asthmatic patients showed that a single IV dose of atenolol 3mg caused slight impairment of ventilatory function. A dose of salbutamol by inhalation was able to reverse the bronchial effect of atenolol.(15) Propranolol (80mg/day), oxprenolol (80mg/day), atenolol (100mg/day), and celiprolol 200mg/day were given to 10 asthmatic patients in a randomized, crossover design with a two week washout period between each drug. The non-beta 1 selective beta blockers (propranolol, oxprenolol) caused a significant reduction in FEV1 and inhibited the bronchodilator response to inhaled salbutamol. Atenolol and celiprolol (beta1 selective beta blockers) did not significantly affect respiratory function or antagonize salbutamol effects.(16) A double blind, randomized, within patient, placebo-controlled study compared the cardioselective beta-blocker atenolol to the non-selective propranolol. Atenolol caused a significantly less drop in FEV1 compared to propranolol. The effect of isoprenaline plus the beta blockers were also studied. Both atenolol and propranolol effected isoprenaline FEV1 dose response curves but the greatest displacement was seen with propranolol.(17) The pulmonary effects of celiprolol 200 mg, celiprolol 400mg, propranolol 40mg, atenolol 100 mg were evaluated in 34 asthmatic patients. Propranolol and atenolol caused significant reductions in pulmonary function. Propranolol pretreatment caused a significant reduction in the effect of the bronchodilator. Celiprolol did not antagonize the bronchodilators.(18) A double-blind, placebo controlled, randomized, crossover design study studied the effects of propranolol 80mg or celiprolol 200 or 400mg on pulmonary function. Propranolol produced a significant decrease in FEV1 and FVC. Celiprolol and placebo had similar results. The effect of aerosolized terbutaline was also measured. Even at supratherapeutic doses, terbutaline was unable to restore pulmonary function parameters to baseline levels after treatment with propranolol. Terbutaline caused further bronchodilation after administration of celiprolol.(19) Eleven asthmatic patients showed significant bronchoconstriction in small airways after propranolol 40mg and pindolol 2.5mg in a double blind, randomized trial. Large airways only showed bronchoconstriction with propranolol. Terbutaline 0.5mg subcutaneous was given after pretreatment with propranolol and pindolol. The bronchodilator effect of terbutaline on large airways was diminished after both propranolol and timolol.(20) |
AIRSUPRA, ALBUTEROL SULFATE, ALBUTEROL SULFATE HFA, ANORO ELLIPTA, ARFORMOTEROL TARTRATE, BEVESPI AEROSPHERE, BREO ELLIPTA, BREYNA, BREZTRI AEROSPHERE, BROVANA, BUDESONIDE-FORMOTEROL FUMARATE, COMBIVENT RESPIMAT, DUAKLIR PRESSAIR, DULERA, FLUTICASONE-VILANTEROL, FORMOTEROL FUMARATE, IPRATROPIUM-ALBUTEROL, LEVALBUTEROL CONCENTRATE, LEVALBUTEROL HCL, LEVALBUTEROL TARTRATE HFA, PERFOROMIST, PROAIR DIGIHALER, PROAIR RESPICLICK, STIOLTO RESPIMAT, STRIVERDI RESPIMAT, SYMBICORT, TERBUTALINE SULFATE, TRELEGY ELLIPTA, UMECLIDINIUM-VILANTEROL, VENTOLIN HFA, XOPENEX HFA |
| Allergen Immunotherapy/Beta-Blockers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Beta-blockers may mask early signs and symptoms of anaphylaxis, make the treatment of anaphylaxis more difficult, and increase the severity of the reaction. CLINICAL EFFECTS: Beta-blockers may reduce a patient's ability to survive a systemic allergic reaction to allergen immunotherapy. Signs and symptoms of anaphylaxis may be masked. PREDISPOSING FACTORS: Concurrent use of epinephrine with beta-blockers may result in hypertension with reflex bradycardia. Epinephrine resistance in patients with anaphylaxis has been reported. PATIENT MANAGEMENT: Avoid concomitant administration of immunotherapy and beta-blockers if possible. If patients cannot safely discontinue beta-blockers but have a history of moderate to severe sting-induced anaphylaxis, venom immunotherapy is indicated because the risk of anaphylaxis related to a venom sting is greater than the risk of an immunotherapy-related systemic reaction. In patients taking beta-blockers for whom an acceptable alternative is not available, withholding allergen immunotherapy may be the best option. If both drugs are administered, monitor closely for signs and symptoms of anaphylaxis. Use caution when treating anaphylaxis with epinephrine since response may be poor. Epinephrine administration may worsen anaphylaxis because beta-blockers block the beta effects of epinephrine, which results in predomination of alpha effects. The plasma clearance of epinephrine is decreased. Glucagon may help in the treatment of refractory anaphylaxis in patients receiving beta-blockers. DISCUSSION: In a case report, a patient taking propranolol was administered pollen extract immunotherapy and immediately developed anaphylaxis. Treatment with epinephrine did not improve symptoms and patient was subsequently intubated.(2) In another case report, a patient taking propranolol was given pollen immunotherapy and developed anaphylaxis. Difficulty in maintaining an adequate blood pressure and pulse continued for several hours despite epinephrine and other supportive measures.(3) There are other case reports of patients taking propranolol with venom immunotherapy that were refractory to treatment.(6-7) |
9 TREE MIX EXTRACT, ACACIA, ALDER, ALFALFA EXTRACT, ALTERNARIA ALTERNATA, AMERICAN BEECH, AMERICAN COCKROACH EXTRACT, AMERICAN ELM, AMERICAN SYCAMORE, ARIZONA CYPRESS, ASPERGILLUS FUMIGATUS, AUREOBASIDIUM PULLULANS, BAHIA, BALD CYPRESS, BAYBERRY, BLACK WALNUT POLLEN, BOTRYTIS CINEREA, BOX ELDER, BROME, CALIFORNIA PEPPER TREE, CANDIDA ALBICANS, CARELESSWEED, CATTLE EPITHELIUM, CEDAR ELM, CLADOSPORIUM CLADOSPORIOIDES, COCKLEBUR, CORN POLLEN, CORN SMUT, D.FARINAE MITE EXTRACT, D.PTERONYSSINUS MITE EXTRACT, DOG EPITHELIUM EXTRACT, DOG FENNEL, EASTERN COTTONWOOD, ENGLISH PLANTAIN, EPICOCCUM NIGRUM, FIRE ANT, GERMAN COCKROACH, GOLDENROD, GRASTEK, GUINEA PIG EPITHELIUM EXTRACT, HACKBERRY, HONEY BEE VENOM PROTEIN, HORSE EPITHELIUM, JOHNSON GRASS, KOCHIA, LAMB'S QUARTERS, MELALEUCA, MESQUITE, MIXED COCKROACH, MIXED FEATHERS, MIXED RAGWEED EXTRACT, MIXED VESPID VENOM PROTEIN, MOSQUITO, MOUNTAIN CEDAR, MOUSE EPITHELIUM, MUCOR PLUMBEUS, MUGWORT, ODACTRA, OLIVE TREE, ORALAIR, PALFORZIA, PECAN POLLEN, PENICILLIUM NOTATUM, PRIVET, QUACK GRASS, QUEEN PALM, RABBIT EPITHELIUM, RAGWITEK, RED BIRCH, RED CEDAR, RED MAPLE, RED MULBERRY, RED OAK, ROUGH MARSH ELDER, ROUGH PIGWEED, RUSSIAN THISTLE, SACCHAROMYCES CEREVISIAE, SAGEBRUSH, SAROCLADIUM STRICTUM, SHAGBARK HICKORY, SHEEP SORREL, SHEEP SORREL-YELLOW DOCK, SHORT RAGWEED, SPINY PIGWEED, STANDARD BERMUDA GRASS POLLEN, STANDARD MIXED GRASS POLLEN, STANDARD MIXED MITE EXTRACT, STANDARD RYE GRASS POLLEN, STANDARD SWEET VERNAL GRASS, STANDARDIZED CAT HAIR, STANDARDIZED JUNE GRASS POLLEN, STANDARDIZED MEADOW FESCUE, STANDARDIZED ORCHARD GRASS, STANDARDIZED RED TOP GRASS, STANDARDIZED TIMOTHY GRASS, SWEETGUM, TALL RAGWEED, TRICHOPHYTON MENTAGROPHYTES, VIRGINIA LIVE OAK, WASP VENOM PROTEIN, WEED MIX NO.7B EXTRACT, WESTERN JUNIPER, WESTERN RAGWEED, WHITE ASH, WHITE BIRCH, WHITE MULBERRY, WHITE OAK EXTRACT, WHITE PINE, WHITE-FACED HORNET VENOM, YELLOW DOCK, YELLOW HORNET VENOM PROTEIN, YELLOW JACKET VENOM PROTEIN |
| Iobenguane I 123/Agents that Affect Catecholamines SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1) CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with imaging completed with iobenguane.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores prior to imaging with iobenguane. Before imaging with iobenguane, discontinue agents that affect catecholamines for at least 5 biological half-lives, as clinically tolerated.(1) DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine) |
ADREVIEW |
| Siponimod/Beta-Blockers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Initiation of siponimod has caused transient decreases in heart rate and atrioventricular conduction delays after the first dose. Decreases in heart rate start within the first hour and maximal decrease in heart rate was seen at approximately 3-4 hours. The first dose has also been associated with heart block. Beta-blockers further increase the risk for symptomatic bradycardia or heart block.(1) CLINICAL EFFECTS: The heart rate lowering effect of siponimod is transient and is usually seen with the first dose. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes.(1) PREDISPOSING FACTORS: Pre-existing cardiovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, history of torsades de pointes, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to siponimod initiation, or factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia, bradycardia, female gender, or advanced age) may increase risk for cardiovascular toxicity due to siponimod. Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) PATIENT MANAGEMENT: The prescribing information states temporary interruption in beta-blocker therapy may be needed before initiation of siponimod. Beta-blocker therapy can be initiated in patients receiving stable doses of siponimod.(1) Treatment initiation recommendations include: - Obtain an ECG in all patients to determine whether preexisting conduction abnormalities are present. - In all patients, a dose titration is recommended for initiation of siponimod treatment to help reduce cardiac effects. - In patients with sinus bradycardia (HR less than 55 bpm), first- or second-degree [Mobitz type I] AV block, or a history of myocardial infarction or heart failure with onset > 6 months prior to initiation, ECG testing and first dose monitoring is recommended. - Since significant bradycardia may be poorly tolerated in patients with history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, or severe untreated sleep apnea, siponimod is not recommended in these patients. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy. - Use of siponimod in patients with a history of recurrent syncope or symptomatic bradycardia should be based on an overall benefit-risk assessment. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring. - For patients receiving a stable dose of a beta-blocker, the resting heart rate should be considered before introducing siponimod treatment. If the resting heart rate is greater than 50 bpm under chronic beta-blocker treatment, siponimod can be introduced. If resting heart rate is less than or equal to 50 bpm, beta-blocker treatment should be interrupted until the baseline heart-rate is greater than 50 bpm. Treatment with siponimod can then be initiated and treatment with a beta-blocker can be reinitiated after siponimod has been up-titrated to the target maintenance dosage. - If a titration dose is missed or if 4 or more consecutive daily doses are missed during maintenance treatment, reinitiate Day 1 of the dose titration and follow titration monitoring recommendations.(1) DISCUSSION: After the first titration dose of siponimod, the heart rate decrease starts within an hour, and the Day 1 decline is maximal at approximately 3-4 hours. With continued up-titration, further heart rate decreases are seen on subsequent days, with maximal decrease from Day 1-baseline reached on Day 5-6. The highest daily post-dose decrease in absolute hourly mean heart rate is observed on Day 1, with the pulse declining on average 5-6 bpm. Post-dose declines on the following days are less pronounced. With continued dosing, heart rate starts increasing after Day 6 and reaches placebo levels within 10 days after treatment initiation. In Study 1, bradycardia occurred in 4.4% of siponimod-treated patients compared to 2.9% of patients receiving placebo. Patients who experienced bradycardia were generally asymptomatic. Few patients experienced symptoms, including dizziness or fatigue, and these symptoms resolved within 24 hours without intervention.(1) Beta-Blockers linked to this monograph are: atenolol, betaxolol, bisoprolol, carvedilol, esmolol, landiolol, labetalol, metoprolol, nadolol, nebivolol, propranolol and timolol. |
MAYZENT |
| Crizotinib/Agents That Cause Bradycardia SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Crizotinib may cause symptomatic bradycardia. Additional agents that cause bradycardia further increase the risk for symptomatic bradycardia.(1) CLINICAL EFFECTS: Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of crizotinib recommends avoiding concurrent use of crizotinib and other agents known to cause bradycardia to the extent possible. If combination therapy is required, monitor heart rate and blood pressure regularly. If bradycardia occurs, withhold crizotinib until heart rate recovers to 60 bpm or above, or patient is asymptomatic. Re-evaluate the use of the concomitant medication. If the concomitant medication is discontinued or its dose is reduced, resume crizotinib at the previous dose upon patient's recovery. If the concomitant medication is not discontinued or dose adjusted, resume crizotinib at a reduced dose upon patient's recovery. If life-threatening bradycardia occurs, discontinue or reduce the dose of the concomitant medication. Upon the patient's recovery, lower the dose of crizotinib to 250 mg daily. Monitor blood pressure and heart rate frequently.(1) DISCUSSION: Across clinical trials, bradycardia occurred in 13 % of patients on crizotinib, and grade 3 syncope occurred in 2.4 % of patients on crizotinib compared with 0.6 % on chemotherapy.(1) Agents that may cause bradycardia and linked to this monograph include: beta-blockers, non-dihydropyridine calcium channel blockers, clonidine, digoxin, and moxonidine.(1) |
XALKORI |
| Ponesimod/Beta-Blockers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Initiation of ponesimod has caused transient decreases in heart rate and atrioventricular conduction delays after the first dose. Decreases in heart rate start within the first hour and maximal decrease in heart rate was seen at approximately 2-4 hours. The first dose has also been associated with heart block. Beta-blockers further increase the risk for symptomatic bradycardia or heart block.(1) CLINICAL EFFECTS: The heart rate lowering effect of ponesimod is transient and is usually seen with the first dose. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes.(1) PREDISPOSING FACTORS: Pre-existing cardiovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, history of torsades de pointes, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to siponimod initiation, or factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia, bradycardia, female gender, or advanced age) may increase risk for cardiovascular toxicity due to siponimod. Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) PATIENT MANAGEMENT: The prescribing information states temporary interruption in beta-blocker therapy may be needed before initiation of ponesimod. Beta-blocker therapy can be initiated in patients receiving stable doses of ponesimod.(1) Treatment initiation recommendations include: - Obtain an ECG in all patients to determine whether preexisting conduction abnormalities are present. - In all patients, a dose titration is recommended for initiation of ponesimod treatment to help reduce cardiac effects. - In patients with sinus bradycardia (HR less than 55 bpm), first- or second-degree [Mobitz type I] AV block, or a history of myocardial infarction or heart failure with onset > 6 months prior to initiation, ECG testing and first dose monitoring is recommended. - Since significant bradycardia may be poorly tolerated in patients with history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, or severe untreated sleep apnea, ponesimod is not recommended in these patients. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy. - Use of ponesimod in patients with a history of recurrent syncope or symptomatic bradycardia should be based on an overall benefit-risk assessment. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring. - For patients receiving a stable dose of a beta-blocker, the resting heart rate should be considered before introducing ponesimod treatment. If the resting heart rate is greater than 55 bpm under chronic beta-blocker treatment, ponesimod can be introduced. If resting heart rate is less than or equal to 55 bpm, beta-blocker treatment should be interrupted until the baseline heart-rate is greater than 55 bpm. Treatment with ponesimod can then be initiated and treatment with a beta-blocker can be reinitiated after ponesimod has been up-titrated to the target maintenance dosage. - If a titration dose is missed or if 4 or more consecutive daily doses are missed during maintenance treatment, reinitiate Day 1 of the dose titration and follow titration monitoring recommendations.(1) DISCUSSION: After the first titration dose of ponesimod the heart rate decrease starts within an hour, and the Day 1 decline is maximal at approximately 2-4 hours. With continued up-titration, further heart rate decreases are seen on subsequent days, with maximal decrease from Day 1-baseline reached on Day 4-5. The highest daily post-dose decrease in absolute hourly mean heart rate is observed on Day 1, with the pulse declining on average 6 bpm. Post-dose declines on the following days are less pronounced. With continued dosing, heart rate starts increasing after Day 6 and reaches placebo levels within 10 days after treatment initiation. In a study, bradycardia occurred in 5.8% of ponesimod-treated patients compared to 1.6% of patients receiving placebo. Patients who experienced bradycardia were generally asymptomatic. Few patients experienced symptoms, including dizziness or fatigue, and these symptoms resolved within 24 hours without intervention.(1) Beta-Blockers linked to this monograph are: atenolol, betaxolol, bisoprolol, carvedilol, esmolol, landiolol, labetalol, metoprolol, nadolol, nebivolol, propranolol and timolol. |
PONVORY |
| Tizanidine/Selected Moderate and Weak CYP1A2 Inhibitors SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Moderate and weak CYP1A2 inhibitors may inhibit the metabolism of tizanidine by CYP1A2.(1) CLINICAL EFFECTS: Concurrent use of moderate and weak CYP1A2 inhibitors may result in elevated levels of and effects from tizanidine, including hypotension, bradycardia, drowsiness, sedation, and decreased psychomotor function. PREDISPOSING FACTORS: The risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(2) PATIENT MANAGEMENT: The US manufacturer of tizanidine states that concurrent use of tizanidine with inhibitors of CYP1A2 should be avoided. If concurrent use is warranted, tizanidine should be initiated with 2 mg dose and increased in 2-4 mg steps daily based on patient response to therapy.(3) If adverse reactions such as hypotension, bradycardia or excessive drowsiness occur, reduce or discontinue tizanidine therapy.(3) DISCUSSION: In a study, cannabidiol 750 mg twice daily (a weak CYP1A2 inhibitor) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a 200 mg single dose of caffeine (a sensitive CYP1A2 substrate) by 15% and 95%, respectively.(1) In a study in 10 healthy subjects, concurrent fluvoxamine, a strong inhibitor of CYP1A2, increased tizanidine Cmax, AUC, and half-life (T1/2) by 12-fold, 33-fold, and 3-fold, respectively. Significant decreases in blood pressure and increases in drowsiness and psychomotor impairment occurred.(3) In a study in 10 healthy subjects, concurrent ciprofloxacin, a strong inhibitor of CYP1A2, increased tizanidine Cmax and AUC by 7-fold and 10-fold, respectively. Significant decreases in blood pressure and increases in drowsiness and psychomotor impairment occurred.(3) Moderate CYP1A2 inhibitors linked to this monograph include: dipyrone, fexinidazole, genistein, methoxsalen, phenylpropanolamine, pipemidic acid, propranolol, rucaparib, and troleandomycin. Weak CYP1A2 inhibitors linked to this monograph include: allopurinol, artemisinin, caffeine, cannabidiol, curcumin, dan-shen, disulfiram, Echinacea, ginseng, parsley, piperine, ribociclib, simeprevir, thiabendazole, and triclabendazole.(4) |
TIZANIDINE HCL, ZANAFLEX |
| Salmeterol/Non-Cardioselective Beta-Blockers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Non-cardioselective beta-blockers and beta-2 agonists may antagonize the effects of each other. CLINICAL EFFECTS: Diminished response to either the beta-agonist, beta-blocker, or both may occur. Beta-blockers may also induce bronchospasm. PREDISPOSING FACTORS: Patients receiving beta-2 agonists for the treatment of asthma may be more at risk for bronchospasm. PATIENT MANAGEMENT: If possible, avoid beta-blocker therapy in asthmatic patients requiring beta-2 agonist therapy. If beta-blocker therapy is required, use a cardio-selective beta-blocker. Monitor patients for decreased effects of either agent, such as increased need for/use of beta-2 agonists or increased heart rate or blood pressure. DISCUSSION: Many patients with asymptomatic or mild reactive airways disease tolerate beta-blockers well. Most patients with COPD do not have bronchospastic component to their illness and may be given beta-blockers. Heart failure treatment guidelines recommend beta-blockers in the presence of COPD. Non-selective beta-blockers have been shown to have a negative effect on lung function (FEV1) and airway hyperresponsiveness (AHR) in patients with asthma and COPD.(1) An open-label study using the nonselective beta blocker nadolol showed no effect on salbutamol in 10 patients with mild asthma not on controller therapy.(2) A study in 8 healthy men showed that long acting propranolol (160 mg) only effected airway dilation at the 200 mcg salbutamol dose. The 800 mcg and 1600 mcg dose were unaffected. However, penbutolol prevented any significant airway dilation with all doses of salbutamol.(3) In a double blind, three-way, crossover study, 44% (7/16 patients) of patients taking metoprolol showed a greater than 20% decrease in FEV1 compared to 19% (3 patients) after dilevalol and 6% (1 patient) after placebo. Dilevalol and metoprolol significantly inhibited isoproterenol response compared to placebo.(4) A double-blind, randomized, crossover study in 10 asthmatic patients showed that intravenous propranolol produced marked symptomatic bronchoconstriction. Only a slight but significant inhibition of bronchomotor sensitivity to isoproterenol was noted during esmolol infusion.(5) In 18 patients with reversible bronchial asthma, labetalol caused a significant increase in FEV1 and metoprolol caused a significant decrease in FEV1. Concurrent administration of isoproterenol and labetalol caused a further increase in FEV1. The effect of isoproterenol was decreased by metoprolol (100, 200mg).(6) In one study propranolol (0.06mg/kg IV) was shown to almost completely block the effects of isoproterenol in asthmatics. Metoprolol (0.12mg/kg IV) did not affect isoproterenol.(7) Studies have shown that cardioselective beta-blockers are safe for patients with asthma and COPD.(8,9,10) Nebivolol and celiprolol significantly decreased FEV1. Inhalation of albuterol (up to 800mcg) significantly improved FEV1, but the values after nebivolol and celiprolol administration were lower than the initial values.(11) Administration of metoprolol did not cause any respiratory problems in 9 asthmatic patients. There was no significant difference between the metoprolol and placebo groups in the respiratory response to an isoproterenol aerosol in 24 asthmatic patients.(12) Eight male asthmatic patients were given 10 mg bisoprolol, 20 mg bisoprolol, and 100 mg metoprolol. Both bisoprolol and metoprolol caused bronchoconstriction measured by a significant fall in PEFR (peak expiratory flow rate). Terbutaline was able to reverse bronchoconstriction in all patients.(13) A double blind, placebo-controlled study analyzed the use of atenolol 100mg, metoprolol 100mg, or acebutolol 400 mg in 8 asthmatic patients before and after exercise. All three drugs reduced significantly FEV1 and PEFR. Administration of terbutaline improved all respiratory indices.(14) A double-blind crossover trial in 10 asthmatic patients showed that a single IV dose of atenolol 3mg caused slight impairment of ventilatory function. A dose of salbutamol by inhalation was able to reverse the bronchial effect of atenolol.(15) Propranolol (80mg/day), oxprenolol (80mg/day), atenolol (100mg/day), and celiprolol 200mg/day were given to 10 asthmatic patients in a randomized, crossover design with a two week washout period between each drug. The non-beta 1 selective beta blockers (propranolol, oxprenolol) caused a significant reduction in FEV1 and inhibited the bronchodilator response to inhaled salbutamol. Atenolol and celiprolol (beta1 selective beta blockers) did not significantly affect respiratory function or antagonize salbutamol effects.(16) A double blind, randomized, within patient, placebo-controlled study compared the cardioselective beta-blocker atenolol to the non-selective propranolol. Atenolol caused a significantly less drop in FEV1 compared to propranolol. The effect of isoprenaline plus the beta blockers were also studied. Both atenolol and propranolol effected isoprenaline FEV1 dose response curves but the greatest displacement was seen with propranolol.(17) The pulmonary effects of celiprolol 200 mg, celiprolol 400mg, propranolol 40mg, atenolol 100 mg were evaluated in 34 asthmatic patients. Propranolol and atenolol caused significant reductions in pulmonary function. Propranolol pretreatment caused a significant reduction in the effect of the bronchodilator. Celiprolol did not antagonize the bronchodilators.(18) A double-blind, placebo controlled, randomized, crossover design study studied the effects of propranolol 80mg or celiprolol 200 or 400mg on pulmonary function. Propranolol produced a significant decrease in FEV1 and FVC. Celiprolol and placebo had similar results. The effect of aerosolized terbutaline was also measured. Even at supratherapeutic doses, terbutaline was unable to restore pulmonary function parameters to baseline levels after treatment with propranolol. Terbutaline caused further bronchodilation after administration of celiprolol.(19) Eleven asthmatic patients showed significant bronchoconstriction in small airways after propranolol 40mg and pindolol 2.5mg in a double blind, randomized trial. Large airways only showed bronchoconstriction with propranolol. Terbutaline 0.5mg subcutaneous was given after pretreatment with propranolol and pindolol. The bronchodilator effect of terbutaline on large airways was diminished after both propranolol and timolol.(20) |
ADVAIR DISKUS, ADVAIR HFA, AIRDUO DIGIHALER, FLUTICASONE-SALMETEROL, FLUTICASONE-SALMETEROL HFA, SEREVENT DISKUS, WIXELA INHUB |
| Etrasimod/Beta-Blockers SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction. MECHANISM OF ACTION: Initiation of etrasimod has caused transient decreases in heart rate and atrioventricular conduction delays after the first dose. The first dose has also been associated with heart block. Beta-blockers further increase the risk for symptomatic bradycardia or heart block.(1) CLINICAL EFFECTS: The heart rate lowering effect of etrasimod is transient and is usually seen with the first dose. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes.(1) PREDISPOSING FACTORS: Pre-existing cardiovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, history of torsades de pointes, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to etrasimod initiation, or factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia, bradycardia, female gender, or advanced age) may increase risk for cardiovascular toxicity due to etrasimod. Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2) PATIENT MANAGEMENT: The prescribing information states etrasimod therapy can be initiated in patients receiving stable doses of beta blocker therapy. Cardiology consultation is recommended before initiating a beta blocker in a patient receiving stable etrasimod treatment.(1) DISCUSSION: Initiation of etrasimod may result in a transient decrease in heart rate and AV conduction delays. In two studies, after the first dose of etrasimod 2 mg, ulcerative colitis patients saw a mean decrease from baseline in heart rate of 7.2 bpm at hour 3 in UC-1 an hour 2 in UC-2.(1) In UC-1, bradycardia was reported on Day 1 in 1% of etrasimod patients, 0.3% on Day 2 compared to no patients receiving placebo.In UC-2 and UC-3, bradycardia was reported on Day 1 in 2.9% of etrasimod patients, 0.3% on Day 2 compared to no patients receiving placebo. Patients experiencing bradycardia were generally asymptomatic. The few patients with symptomatic bradycardia reported dizziness that resolved without intervention.(1) Beta-Blockers linked to this monograph are: atenolol, betaxolol, bisoprolol, carvedilol, esmolol, labetalol, landiolol, metoprolol, nadolol, nebivolol, propranolol and timolol. |
VELSIPITY |
There are 27 moderate interactions.
The clinician should assess the patient’s characteristics and take action as needed. Actions required for moderate interactions include, but are not limited to, discontinuing one or both agents, adjusting dosage, altering administration.
| Drug Interaction | Drug Names |
|---|---|
| Selected Beta-Blockers/Theophyllines SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Certain beta-blockers may inhibit theophylline metabolism. In addition, beta-blockers, especially non-selective agents, can antagonize the pharmacologic effects of theophylline. CLINICAL EFFECTS: Even though theophylline concentrations may increase leading to increased possibility of theophylline toxicity, beta-blockers decrease theophylline's therapeutic effects. PREDISPOSING FACTORS: Cigarette smoking may exacerbate this interaction. PATIENT MANAGEMENT: Avoid the use of non-selective beta-blockers with theophylline. If a beta-blocker must be used, a cardioselective agent that does not decrease the clearance of theophylline (e.g., atenolol) should be considered. However, since cardioselectivity is not absolute and is less selective at higher doses, cardioselective beta-blockers should be used with caution in patients with bronchospastic disease. DISCUSSION: Inhibition of theophylline metabolism is greatest with lipophilic beta-blockers undergoing hepatic metabolism (e.g., propranolol). Additionally, the decrease in theophylline clearance appears to be dose dependent as the higher the beta-blocker dose, the greater the decrease in theophylline clearance. If the patient is on both drugs and the beta-blocker is discontinued, serum theophylline concentrations may decrease. In these cases, monitor for a decrease in theophylline therapeutic effect and adjust the dose as needed. |
AMINOPHYLLINE, DYPHYLLINE, THEO-24, THEOPHYLLINE, THEOPHYLLINE ANHYDROUS, THEOPHYLLINE ER, THEOPHYLLINE ETHYLENEDIAMINE |
| Sulfonylureas/Systemic Non-Cardioselective Beta-Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Not fully established. Probably blockade of a variety of beta-adrenergic responses to hypoglycemia. CLINICAL EFFECTS: Diminished response to sulfonylureas and insulin may occur. Frequency and severity of hypoglycemic episodes may be increased, while warning symptoms of low blood sugar may be masked. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Try to avoid beta-blocker therapy, particularly in diabetics prone to hypoglycemic attacks. One of the cardioselective agents may decrease risk of hypertensive attacks and allow more rapid glucose recovery from hypoglycemia. Patients should be counseled not to rely on tachycardia to diagnose hypoglycemia, since it is masked by beta-blocker therapy. Diaphoresis is unaffected by beta-blockade and can be used by the diabetic to recognize hypoglycemia. DISCUSSION: A class effect of diminished glucose-lowering effects is expected with concurrent use of beta-blockers and sulfonylureas. It is prudent to monitor serum glucose closely in patients receiving beta-blocker therapy because symptoms of hypoglycemia may be masked. A double blind, randomized, 12 month study of 39 patients tested the metabolic effects of pindolol (5 mg BID) compared to control group on insulin sensitivity. The patient's insulin sensitivity index decreased 17% when on pindolol treatment compared to placebo (p<0.01). Insulin mediated glucose uptake was significantly lower (p<0.05) with propranolol treatment than with placebo.(1) A study of 26 patients with chronic heart failure showed that carvedilol (average daily dose 27.5 mg/d) caused a significant decrease in fasting insulin levels (17.09 to 10.77 microU/ml, p <0.05) compared to pre-treatment levels. This trial also showed that patients on carvedilol had significantly (p=0.015) lower fasting insulin levels (10.77 microU/ml) compared to the fasting insulin levels (20.72 microU/ml) of patients on bisoprolol treatment (5.9mg/d).(2) |
DUETACT, GLIMEPIRIDE, GLIPIZIDE, GLIPIZIDE ER, GLIPIZIDE XL, GLIPIZIDE-METFORMIN, GLYBURIDE, GLYBURIDE MICRONIZED, GLYBURIDE-METFORMIN HCL, PIOGLITAZONE-GLIMEPIRIDE |
| Selected Beta-Blockers/Barbiturates SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Induction of hepatic microsomal enzymes by barbiturates decreases bioavailability of oral beta-blockers which are extensively metabolized (e.g., propranolol, metoprolol). Primidone is metabolized to phenobarbital. CLINICAL EFFECTS: May observe reduced therapeutic response to those beta-blockers metabolized by the liver (e.g., increased pulse rate and increase in systolic and diastolic blood pressures). PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks. PATIENT MANAGEMENT: Caution when barbiturates are started or stopped. Adjust dosage of beta-blocker if necessary. This interaction may be avoided by using beta-blockers primarily excreted unchanged by the kidneys (e.g., atenolol, nadolol). DISCUSSION: The effect of this interaction may be seen in 4 to 5 days after starting barbiturate therapy. If the barbiturate is given for less than 3 days a clinically important interaction is unlikely. Serum concentration of the beta-blocker may increase when the barbiturate is discontinued. Additional documentation is necessary to confirm this potential interaction for individual beta-blockers. |
ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, BUTALB-ACETAMINOPH-CAFF-CODEIN, BUTALBITAL, BUTALBITAL-ACETAMINOPHEN, BUTALBITAL-ACETAMINOPHEN-CAFFE, BUTALBITAL-ASPIRIN-CAFFEINE, DONNATAL, FIORICET, MYSOLINE, PENTOBARBITAL SODIUM, PHENOBARBITAL, PHENOBARBITAL SODIUM, PHENOBARBITAL-BELLADONNA, PHENOBARBITAL-HYOSC-ATROP-SCOP, PHENOHYTRO, PRIMIDONE, SEZABY, TENCON |
| Metoprolol; Propranolol/Cimetidine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Cimetidine inhibition of CYP2D6 may reduce the metabolism of metoprolol and propranolol. CLINICAL EFFECTS: Concurrent use of cimetidine may result in increased pharmacologic and toxic side effects of metoprolol and propranolol. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Lower dosages of metoprolol and propranolol may be required in patients receiving cimetidine. When initiating cimetidine in a patient maintained on metoprolol or propranolol, observe the patient for increased beta-blocker effects such as lower heart rate and blood pressure. Consider lower starting doses of metoprolol or propranolol in patients receiving cimetidine. A dosage adjustment of the beta-blocker may be necessary when initiating or discontinuing cimetidine. Since other H-2 antagonists (e.g., ranitidine, famotidine) do not appear to interact, substituting cimetidine with one of these agents may be desirable. However, if a patient is already receiving this combination and is not experiencing adverse effects, substitution is probably not necessary. DISCUSSION: Concurrent administration of cimetidine (1G/day to 1.2G/day) and propranolol has resulted in approximately a two-fold increase in propranolol plasma concentrations as well as an increase in its area-under-curve (AUC) and half-life after single (80mg) or multiple (160mg/day) doses. The alterations in propranolol levels were seen within 24 to 48 hours.(1-12) Concurrent administration of cimetidine increased the AUC of metoprolol by 60% to 70%.(11-17) |
CIMETIDINE |
| Lidocaine/Beta-Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Decreased cardiac output and hepatic blood flow due to beta-blockers may result in reduced elimination of lidocaine. Inhibition of hepatic microsomal enzymes may also contribute to decreased lidocaine clearance. CLINICAL EFFECTS: Lidocaine toxicity is more likely to occur when these drugs are used in combination. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The lidocaine dose may need to be adjusted when a beta-blocker is added or discontinued. Clinical signs of lidocaine toxicity and lidocaine plasma levels should be monitored. DISCUSSION: The effect seems to be more pronounced in the lipid soluble beta-blockers (eg. propranolol, metoprolol). |
LIDOCAINE, LIDOCAINE HCL, LIDOCAINE HCL IN 5% DEXTROSE |
| Selected Beta-blockers/Selected Calcium Channel Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Synergistic pharmacologic activity. CLINICAL EFFECTS: May see an increase in the therapeutic and toxic effects of both drugs. Concurrent use in patients with low heart rates may unmask sick sinus syndrome. PREDISPOSING FACTORS: Preexisting left ventricular dysfunction and high doses of the beta-blocking agent may predispose patients to adverse responses to this drug combination. Other possible factors include parenteral administration and concurrent administration of other cardio-depressant drugs such as antiarrhythmics. PATIENT MANAGEMENT: Monitor the patient for signs of increased cardio-depressant effects and hypotension. Adjust the dose accordingly. DISCUSSION: Coadministration of these classes of drugs may be effective in the treatment of angina pectoris and hypertension. Patients should be screened in order to determine who should receive this combination of agents. The concurrent use of mibefradil and beta-blockers in patients with low heart rates may unmask underlying sick sinus syndrome. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
CARDIZEM, CARDIZEM CD, CARDIZEM LA, CARTIA XT, DILT-XR, DILTIAZEM 12HR ER, DILTIAZEM 24HR ER, DILTIAZEM 24HR ER (CD), DILTIAZEM 24HR ER (LA), DILTIAZEM 24HR ER (XR), DILTIAZEM HCL, DILTIAZEM HCL-0.7% NACL, DILTIAZEM HCL-0.9% NACL, DILTIAZEM HCL-NACL, DILTIAZEM-D5W, MATZIM LA, NIFEDIPINE, NIFEDIPINE ER, NIFEDIPINE MICRONIZED, PROCARDIA XL, TIADYLT ER, TIAZAC, TRANDOLAPRIL-VERAPAMIL ER, VERAPAMIL ER, VERAPAMIL ER PM, VERAPAMIL HCL, VERAPAMIL SR |
| NSAIDs; Aspirin (Non-Cardioprotective)/Beta-Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Unknown; however, possibly related to inhibition of prostaglandin by NSAIDs. CLINICAL EFFECTS: The antihypertensive action of beta-blockers may be decreased. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor patient's blood pressure and adjust the dose of the beta-blocker as needed. DISCUSSION: Concurrent administration of beta-blockers and NSAIDs has been associated with a clinically significant loss in antihypertensive response. The magnitude of the effect of NSAIDs on control of blood pressure by beta-blockers needs to be determined for each anti-inflammatory agent. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology. |
ACETYL SALICYLIC ACID, ANAPROX DS, ARTHROTEC 50, ARTHROTEC 75, ASA-BUTALB-CAFFEINE-CODEINE, ASCOMP WITH CODEINE, ASPIRIN, BISMUTH SUBSALICYLATE, BROMFENAC SODIUM, BUPIVACAINE-KETOROLAC-KETAMINE, BUTALBITAL-ASPIRIN-CAFFEINE, CALDOLOR, CARISOPRODOL-ASPIRIN, CARISOPRODOL-ASPIRIN-CODEINE, CELEBREX, CELECOXIB, CHOLINE MAGNESIUM TRISALICYLAT, COMBOGESIC, COMBOGESIC IV, CONSENSI, COXANTO, DICLOFENAC, DICLOFENAC POTASSIUM, DICLOFENAC SODIUM, DICLOFENAC SODIUM ER, DICLOFENAC SODIUM MICRONIZED, DICLOFENAC SODIUM-MISOPROSTOL, DIFLUNISAL, DISALCID, DOLOBID, EC-NAPROSYN, ELYXYB, ETODOLAC, ETODOLAC ER, FELDENE, FENOPROFEN CALCIUM, FENOPRON, FLURBIPROFEN, HYDROCODONE-IBUPROFEN, IBU, IBUPAK, IBUPROFEN, IBUPROFEN LYSINE, IBUPROFEN-FAMOTIDINE, INDOCIN, INDOMETHACIN, INDOMETHACIN ER, INFLAMMACIN, INFLATHERM(DICLOFENAC-MENTHOL), KETOPROFEN, KETOPROFEN MICRONIZED, KETOROLAC TROMETHAMINE, LODINE, LOFENA, LURBIRO, MB CAPS, MECLOFENAMATE SODIUM, MEFENAMIC ACID, MELOXICAM, NABUMETONE, NABUMETONE MICRONIZED, NALFON, NAPRELAN, NAPROSYN, NAPROTIN, NAPROXEN, NAPROXEN SODIUM, NAPROXEN SODIUM CR, NAPROXEN SODIUM ER, NAPROXEN-ESOMEPRAZOLE MAG, NEOPROFEN, NORGESIC, NORGESIC FORTE, ORPHENADRINE-ASPIRIN-CAFFEINE, ORPHENGESIC FORTE, OXAPROZIN, PHENYL SALICYLATE, PHENYLBUTAZONE, PIROXICAM, R.E.C.K.(ROPIV-EPI-CLON-KETOR), RELAFEN DS, ROPIVACAINE-CLONIDINE-KETOROLC, ROPIVACAINE-KETOROLAC-KETAMINE, SALSALATE, SODIUM SALICYLATE, SPRIX, SULINDAC, SUMATRIPTAN SUCC-NAPROXEN SOD, SYMBRAVO, TOLECTIN 600, TOLMETIN SODIUM, TORONOVA II SUIK, TORONOVA SUIK, TOXICOLOGY SALIVA COLLECTION, TRESNI, TREXIMET, URIMAR-T, URNEVA, VIMOVO, VIVLODEX, XIFYRM, ZIPSOR, ZORVOLEX, ZYNRELEF |
| Selected Beta-Blockers/Selected Alpha-Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Alpha-blockers may cause syncope with sudden loss of consciousness secondary to excessive postural hypotension. Following the first dose of an alpha-blocker, compensatory tachycardia helps to prevent or limit syncope. Beta-blockers may inhibit this tachycardia, thereby worsening alpha-blocker induced hypotension. CLINICAL EFFECTS: The hypotensive effects of an alpha-blocker may be increased in patients on concurrent beta-blocker therapy. PREDISPOSING FACTORS: Patients may be at increased risk of postural hypotension with concurrent diuretic therapy and those on low-sodium diets. PATIENT MANAGEMENT: When starting alpha-blocker therapy in patients receiving beta-blockers, consider initiating treatment with a reduced dose of the alpha-blocker. If syncope occurs, provide supportive treatment as necessary. The adverse effect is self limiting and in most cases does not recur after the initial period of therapy or during subsequent dose titration with the alpha-blocker. DISCUSSION: Beta-blockers increase the acute postural hypotension that frequently follows the first dose of an alpha-blocker. Initiation of beta-blocker therapy in patients that have started taking an alpha-blocker would not be expected to produce acute postural hypotension. Alpha-blockers linked to this interaction include alfuzosin, doxazosin, prazosin, and terazosin. Beta-blockers linked to this interaction include acebutolol, atenolol, betaxolol, bevantolol, levobunolol, metoprolol, nadolol, pindolol, pronethalol, propranolol, and timolol. |
ALFUZOSIN HCL ER, CARDURA, CARDURA XL, DOXAZOSIN MESYLATE, PRAZOSIN HCL, TERAZOSIN HCL, TEZRULY, UROXATRAL |
| Beta-Blockers, Oral/Rifamycins SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Rifampin is a well recognized enzyme inducer that increases the clearance of many drugs that are metabolized.(1) Beta-blockers that are extensively metabolized may be affected by rifampin. CLINICAL EFFECTS: Decreased pharmacologic effects of certain beta-blockers. PREDISPOSING FACTORS: Dose ranging of rifampin did not suggest a dose proportional interaction.(2) PATIENT MANAGEMENT: Monitor the patient's response to beta-blocker therapy when starting or stopping treatment with rifampin and adjust the dose accordingly. DISCUSSION: Controlled studies involving healthy volunteers have demonstrated rifampin to increase the clearance of metoprolol and propranolol by more than two fold.(2),(3),(4) Steady state plasma concentrations of propranolol were also reduced. The elimination half-life and protein binding of propranolol were not altered by rifampin. In a study in eight subjects, the concurrent administration of rifampin and carvedilol decreased carvedilol concentrations by 70%.(5) |
PRIFTIN, RIFABUTIN, RIFADIN, RIFAMPIN, TALICIA |
| Clonidine/Beta-Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Withdrawal of clonidine triggers increased catecholamine release. Beta-blockers inhibit the vasodilation mediated by the beta 2 receptor, leaving the vasoconstriction mediated by the alpha 2 receptor unopposed. In addition, concurrent use is expected to produce additive effects on blood pressure and heart rate requiring standard monitoring precautions. CLINICAL EFFECTS: Severe hypertension may occur upon abrupt discontinuation of clonidine in patients receiving both clonidine and beta-blockers. In addition, concurrent use is expected to produce additive effects on blood pressure and heart rate requiring standard monitoring precautions. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: In a patient receiving both drugs, discontinuation of the beta-blocker prior to clonidine may decrease the occurrence of rebound hypertension. If clonidine is discontinued first, rebound hypertension can be treated by restarting the clonidine or by the IV administration of phentolamine, phenoxybenzamine or prazosin. When adding either of these agents to the drug regimen of the patient, monitor blood pressure. Since labetalol has both alpha and beta activity, administration of labetalol may prevent rebound hypertension in patients undergoing clonidine withdrawal, although conflicting reports exist. In addition, concurrent use is expected to produce additive effects on blood pressure and heart rate requiring standard monitoring precautions. DISCUSSION: Increased blood pressure has been observed in patients following: 1) the discontinuation of clonidine in patients receiving beta-blockers, 2) the replacement of clonidine therapy with beta-blockers, 3) the simultaneous discontinuation of both drugs. Conflicting reports exist on the development of increased blood pressure after clonidine withdrawal in patients receiving labetalol. Patients receiving labetalol who are being withdrawn from clonidine should still be closely monitored. |
CATAPRES-TTS 1, CATAPRES-TTS 2, CATAPRES-TTS 3, CLONIDINE, CLONIDINE HCL, CLONIDINE HCL ER, DURACLON, NEXICLON XR, ONYDA XR, R.E.C.K.(ROPIV-EPI-CLON-KETOR), ROPIVACAINE-CLONIDINE-KETOROLC |
| Mefloquine; Quinidine/Beta-Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Quinidine may inhibit the oxidative metabolism of beta-blockers. In addition, beta-blockers and quinidine exert a negative inotropic action on the heart. Mefloquine is a chemical analogue of quinine which possess 20% of the antifibrillatory action of quinidine. Alterations in electrocardiograms have been observed during mefloquine therapy. CLINICAL EFFECTS: The pharmacologic effects of certain beta-blockers may be increased during concurrent therapy with quinidine. During concurrent therapy with mefloquine, electrocardiographic abnormalities or cardiac arrest may occur. PREDISPOSING FACTORS: Cardiac disease. PATIENT MANAGEMENT: Monitor the response of the patient and adjust the dose of the beta-blocker as needed. The benefits of mefloquine therapy in patients with preexisting cardiac disease should be weighed carefully. DISCUSSION: Quinidine and beta-blockers have been used therapeutically to treat cardiac arrhythmias; however, they should be used cautiously since quinidine and beta-blockers exert a negative inotropic action on the heart. Quinidine has been associated with an increase in serum metoprolol levels. A reduction in propranolol clearance has been demonstrated in one study, although others have failed to show an interaction between propranolol and quinidine. A patient using timolol eyedrops developed bradycardia following administration of quinidine. There is one report of cardiac arrest, which was successfully treated, in a patient receiving concurrent mefloquine and propranolol. The manufacturer of mefloquine states that concurrent use may produce electrocardiographic abnormalities and cardiac arrest. The manufacturer also recommends weighing the benefits of mefloquine therapy against the risk of adverse effects in patients with cardiac disease. |
MEFLOQUINE HCL, NUEDEXTA, QUINIDINE GLUCONATE, QUINIDINE SULFATE |
| Rizatriptan/Propranolol SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism is unknown. CLINICAL EFFECTS: Concurrent administration of rizatriptan and propranolol may increase the levels of rizatriptan.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: For adult patients receiving propranolol, the manufacturer of rizatriptan states that the 5 mg dose of rizatriptan should be used and that a maximum of three doses (15 mg) should be administered in a 24 hour period.(1) For pediatric patients receiving propranolol who weigh less than 40 kg (88 lb), rizatriptan should not be given.(1) For pediatric patients receiving propranolol who weigh at least 40 kg (88 lb), a single 5 mg dose of rizatriptan is recommended (maximum dose of 5 mg in a 24 hour period).(1) DISCUSSION: In a study in 11 subjects, the concurrent use of rizatriptan (10 mg) with propranolol (240 mg daily) resulted in an increase in the area-under-curve (AUC) of rizatriptan by 70%. A 4-fold increase was observed in one subject. The AUC of the rizatriptan N-monodesmethyl metabolite was not affected by the concurrent administration of propranolol.(1,2) In a study in 12 healthy subjects, concurrent use of propranolol (80 mg twice daily) with almotriptan (12.5 mg) resulted in statistically significant changes in almotriptan AUC; however, the change was less than 7% and considered unlikely to be clinically significant.(3) In a study in 10 healthy subjects, concurrent propranolol (80 mg twice daily) with sumatriptan (300 mg) had no effects on the pharmacokinetics or pharmacodynamics of sumatriptan.(4) In a study in 12 healthy subjects, concurrent use of propranolol (160 mg daily) with zolmitriptan (10 mg) increased the AUC and maximum concentration (Cmax) of zolmitriptan by 56% and 37%, respectively. Propranolol had no effect on the pressor response to zolmitriptan. The authors stated that the effects are unlikely to be clinically significant and that no dosage adjustment is required during concurrent therapy.(5) |
MAXALT, MAXALT MLT, RIZATRIPTAN, SYMBRAVO |
| Selected Anticoagulants (Vit K antagonists)/Propranolol SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The exact mechanism of this interaction is unknown. Propranolol may inhibit the hepatic metabolism of warfarin. CLINICAL EFFECTS: Increased serum concentrations of warfarin may result in an increased risk for bleeding. PREDISPOSING FACTORS: Risk for bleeding episodes may be greater in patients with disease-associated bleeding risk (e.g. thrombocytopenia). Drug risk factors include concurrent use of multiple drugs which inhibit warfarin metabolism, or have an inherent risk for bleeding (e.g. NSAIDs). Patients with a CYP2C9 intermediate metabolizer genotype, and/or 1-2 copies of a reduced function VKORC1 gene are expected to be more susceptible to this interaction. Although patients with a pre-existing CYP2C9 poor metabolizer genotype are expected to be less susceptible to effects from this drug combination, their reduced function genotypes (e.g. CYP2C9 *1/*3, *2/*2, *2/*3, and *3/*3) result in an inherently higher warfarin half-life and risk for warfarin-associated bleeding. CYP2C9 poor metabolizers generally require lower anticoagulant doses and more time (>2 to 4 weeks) to achieve effective and safe anticoagulation than patients without these CYP2C9 variants PATIENT MANAGEMENT: Monitor the INR when propranolol is added to or discontinued from warfarin therapy, particularly when higher doses of propranolol (> 80 mg/dose) are prescribed. If concurrent therapy is warranted, monitor patients receiving concurrent therapy for signs of blood loss, including decreased hemoglobin, hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. When applicable, perform agent-specific laboratory test (e.g. INR, aPTT) to monitor efficacy and safety of anticoagulation. Discontinue anticoagulation in patients with active pathologic bleeding. Instruct patients to report any signs and symptoms of bleeding, such as unusual bleeding from the gums or nose; unusual bruising; red or black, tarry stools; red, pink or dark brown urine; acute abdominal or joint pain and/or swelling. The time of highest risk for a coumarin-type drug interaction is when the precipitant drug is initiated or discontinued. Contact the prescriber before initiating, altering the dose or discontinuing either drug. DISCUSSION: In two studies in healthy subjects, concurrent administration of warfarin and propranolol 80 mg every 12 hours resulted in increases of warfarin area-under-curve (AUC) by 14.7-16.3% and 23% increase in warfarin maximum concentration (Cmax). There were no significant changes in prothrombin times. In a case report, a patient's prothrombin time increased after the addition of propranolol to his warfarin therapy. The prothrombin time decreased to pre-propranolol treatment values when propranolol was discontinued. Studies have shown that warfarin AUC was unaffected by atenolol, metoprolol, or esmolol. Warfarin Cmax was unaffected by metoprolol and esmolol, but increased 12.5% with concurrent administration of atenolol. Prothrombin time, plasma clotting factor VII activity, and the mean warfarin elimination half-life were unchanged by either metoprolol or atenolol. In a study, administration of acebutolol did not result in a significant change in prothrombin time. |
ANISINDIONE, JANTOVEN, WARFARIN SODIUM |
| Beta-Blockers/Propafenone SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Propafenone increases the serum concentration of certain beta-blockers (e.g., metoprolol and propranolol) by decreasing the first-pass metabolism and by inhibition of metabolism. CLINICAL EFFECTS: The pharmacologic effect of certain beta-blockers may be increased. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor cardiac function of patients receiving beta-blockers when starting or stopping propafenone. Adjust the dose of the beta-blocker accordingly. DISCUSSION: Serum concentrations of both metoprolol and propranolol have been found to be increased by concurrent administration of propafenone. A twofold increase in the steady state plasma level of propranolol was measured while metoprolol concentrations increased from two to fivefold. |
PROPAFENONE HCL, PROPAFENONE HCL ER |
| Selected Beta-Blockers/Amiodarone; Dronedarone SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: The mechanism by which carvedilol, metoprolol, nebivolol, and propranolol and amiodarone produce severe bradycardia and hypotension is due to depressant effects on the sinus and AV node. Since these beta-blockers are cleared by CYP2D6 metabolism and amiodarone is a weak 2D6 inhibitor; amiodarone may decrease their metabolism.(1,3) Dronedarone is a moderate CYP2D6 inhibitor therefore may inhibit the metabolism of carvedilol, metoprolol, nebivolol and propranolol since these beta-blockers are cleared by CYP2D6 metabolism.(2-3) CLINICAL EFFECTS: The concurrent administration of hepatically metabolized beta-blockers with amiodarone(1) or dronedarone may result in bradycardia and hypotension.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Use low doses of beta-blockers initially. Only increase the dosage of the beta-blocker after ECG verification of good tolerability.(2) Patients receiving a concurrent therapy should be closely monitored for adverse effects, such as bradycardia and hypotension. Patients experiencing this drug interaction should have their beta-adrenergic blocking drug discontinued. Supportive therapy with sympathomimetic agents may be required. DISCUSSION: In one case report, a patient taking amiodarone developed hypotension and atropine-resistant sinus bradycardia after receiving a single dose of metoprolol. Three hours after receiving the metoprolol dose, the patient experienced dizziness, weakness, and blurred vision.(1) Another report described two patients who exhibited an interaction between amiodarone and propranolol. One patient maintained on amiodarone experienced cardiac arrest after a single oral dose of propranolol. The second patient received intravenous amiodarone followed by 2 doses of oral propranolol and developed severe bradycardia followed by ventricular fibrillation.(4) The stereoselective effect of amiodarone on the pharmacokinetics of racemic carvedilol was evaluated in 106 patients, where 52 received carvedilol monotherapy and 54 received carvedilol with amiodarone. There was no significant differences between the serum concentration to dose ratio between the 2 groups. However, there was an increase in the ratio of S-carvedilol to R-carvedilol. During amiodarone, the concentration of S-carvedilol increased from 3.03 ng/ml to 6.54 ng/ml.(5) Several studies have shown that the addition of carvedilol to congestive heart failure patients currently receiving amiodarone resulted in improved hypotension/dizziness, primary AV block, and aggravated angina.(6-8) Dronedarone increased propranolol and metoprolol (exact dosages not stated) by 1.3-fold and 1.6-fold, respectively.(2) Amiodarone increased metoprolol maximum concentration (Cmax) from 40 mcg/L to 70 mcg/L and area-under-curve (AUC) from 767 mcg x h/L to 1387 mcg x h/L after an amiodarone loading dose of 1.2 g. The interaction was noted to be more pronounced in patients with >/= 2 compared to 1 functional CYP2D6 alleles.(9) Concomitant use of dronedarone and metoprolol were studied in 49 health subjects with four differing CYP2D6 mutations. Thirty-nine were extensive metabolizers of CYP2D6 with Cmax significantly increased from baseline (134.1 ng/mL) on day 13 to 162.6 ng/mL, 195.58 ng/mL, and 180.9 ng/mL after administration of dronedarone 800 mg, 1200 mg, and 1600 mg dose, respectively.(10) |
AMIODARONE HCL, AMIODARONE HCL-D5W, MULTAQ, NEXTERONE, PACERONE |
| Chlorpromazine/Pindolol; Propranolol SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Pindolol and propranolol may inhibit the metabolism of chlorpromazine. Chlorpromazine may inhibit the metabolism of pindolol. CLINICAL EFFECTS: Increased plasma levels with resultant enhanced pharmacologic response of each or both drugs as well as increased risk of toxicity. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: If both drugs are administered, adjust the dose of one or both drugs as needed based on patient response. Dosage adjustments may also be required if one agent is discontinued. DISCUSSION: In study in five subjects, propranolol's bioavailability increased up to 33% with concurrent chlorpromazine administration. The plasma levels of propranolol were increased in three of the subjects.(1) Conversely, chlorpromazine levels have been reported to increase with concomitant propranolol therapy.(2,3) In one study, ten patients received propranolol (mean dose 8.1 mg/Kg/day) and chlorpromazine (mean dose 6.7 mg/Kg/day). In six of the patients, chlorpromazine levels increased five-fold compared to chlorpromazine alone; the active metabolites of chlorpromazine were increased as well.(2) In a case report, a patient maintained on chlorpromazine (800 mg/day) and thiothixene developed delirium, hallucinations, a grand mal seizure, and photosensitivity two weeks after the initiation of propranolol (1200 mg/day). When propranolol was discontinued and the dose of chlorpromazine was decreased, the patient's symptoms resolved.(3) In another study in seven patients, pindolol levels were found to be increased when administered with thioridazine.(4) |
CHLORPROMAZINE HCL |
| Propranolol/Zileuton SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Zileuton may inhibit the metabolism of propranolol by CYP1A2.(1) CLINICAL EFFECTS: Concurrent use of zileuton may result in increased levels of and effects from propranolol.(2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Patient receiving concurrent therapy with zileuton and propranolol should be closely monitored for adverse effects. The dosage of propranolol may need to be adjusted if zileuton is initiated or discontinued.(2) DISCUSSION: In a study in 16 healthy males, pretreatment with zileuton (600 mg ever 6 hours for 5 days) increased the maximum concentration (Cmax), area-under-curve (AUC), and half-life (T1/2) of a single dose of propranolol (80 mg) by 52%, 104%, and 25%, respectively. During concurrent administration, beta-blockade was increased and heart rate was decreased.(2) A study in human liver microsomes showed that zileuton inhibited the metabolism of propranolol by CYP1A2.(1) |
ZILEUTON ER, ZYFLO |
| Selected CYP2D6 Substrates/Terbinafine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Terbinafine is a strong inhibitor of CYP2D6 and may convert patients from the extensive metabolizer to poor metabolizer phenotype for this enzyme.(1) CLINICAL EFFECTS: Concurrent use of terbinafine may result in increased serum levels and adverse effects of drugs primarily metabolized by or sensitive to changes in the activity of the CYP2D6 metabolic pathway.(1,2) PREDISPOSING FACTORS: With paroxetine, the risk of anticholinergic toxicities including cognitive decline, delirium, falls and fractures is increased in geriatric patients using more than one medicine with anticholinergic properties.(3) PATIENT MANAGEMENT: Terbinafine has a serum half-life of approximately 36 hours, so the maximal effect of this interaction may be delayed for one to two weeks. Extended monitoring may be necessary. Patients receiving therapy with agents primarily metabolized by CYP2D6 need increased monitoring for adverse effects and may need a dose reduction. Plasma level monitoring should be considered in patients receiving flecainide.(4) The effect of terbinafine on CYP2D6 substrates may last for up to four weeks after terbinafine discontinuation. Over time, patients previously stabilized on the combination of terbinafine and a selected CYP2D6 substrate may need an increase in the dose of the CYP2D6 metabolized drug. DISCUSSION: In a randomized, placebo-controlled trial in 12 healthy subjects, terbinafine (150 mg daily for 6 days) increased the area-under-curve (AUC) and maximum concentration (Cmax) of a single dose of paroxetine (20 mg) by 2.9-fold and 1.9-fold, respectively.(6) In a placebo-controlled trial in 12 healthy males, terbinafine (250 mg for 4 days) increased the Cmax and AUC of a single dose of venlafaxine (75 mg) by 2.67-fold and 4.9-fold, respectively.(7) CYP2D6 substrates linked to this monograph are: dapoxetine, flecainide, metoprolol, nebivolol, paroxetine, perphenazine, propafenone, propranolol, venlafaxine and yohimbine. |
TERBINAFINE HCL |
| Selected MAOIs/Selected Antihypertensive Agents SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Both MAOIs and antihypertensive agents may increase the risk of postural hypotension.(1,2) CLINICAL EFFECTS: Postural hypotension may occur with concurrent therapy of MAOIs and antihypertensive agents.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The manufacturer of phenelzine states all patients should be followed closely for symptoms of postural hypotension. Hypotensive side effects have occurred in patients who have been hypertensive and normotensive, as well as hypotensive at initiation of phenelzine.(1) The manufacturer of tranylcypromine states hypotension has been observed most commonly but not exclusively in patients with pre-existing hypertension. Tranylcypromine doses greater than 30 mg daily have a major side effect of postural hypotension and can lead to syncope. Gradual dose titration is recommended to decrease risk of postural hypotension. Combined use with other agents known to cause hypotension have shown to have additive side effects and should be monitored closely.(2) Monitor the patient for signs and symptoms of postural hypotension including dizziness, lightheadedness, or weakness, especially upon standing. Monitor blood pressure as well as orthostatic vitals and adjust antihypertensive therapy, including decreasing the dose, dividing doses, or scheduling doses at bedtime, as needed to maintain goal blood pressure. If blood pressure remains hypotensive, consider decreasing the dose of phenelzine or tranylcypromine. In some cases, discontinuation of one or both agents may be necessary.(3) Normotensive patients on stable antihypertensive therapy who are started on either phenelzine or tranylcypromine may be at increased risk for hypotension. Hypertensive patients on stable phenelzine or tranylcypromine who require antihypertensive therapy would be at decreased risk for hypotension. DISCUSSION: A review article describes the pharmacology of phenelzine and tranylcypromine as non-selective MAOIs which inhibit both type A and type B substrates. Orthostatic hypotension is described as the most common MAOI side effect and usually occurs between initiation and the first 3-4 weeks of therapy.(3) In a double-blind study, 71 patients were randomized to receive a 4-week trial of either tranylcypromine, amitriptyline, or the combination. The number of patients reporting dizziness at 4 weeks was not different between the three treatment groups (tranylcypromine 52.4%; amitriptyline 65%; combination 66.7%). Blood pressure (BP) assessment noted a significant drop in standing BP in the tranylcypromine group compared to baseline (systolic BP change = -10 mmHg; p<0.02 and diastolic BP change = -9 mmHg; p<0.02). Combination therapy also had a significant drop in standing BP compared to baseline (systolic BP change = -9 mmHg; p<0.02). Patients receiving amitriptyline had no significant change in BP from baseline at 4 weeks. All three groups had a trend toward increasing orthostatic hypotension in BP changes from lying to standing. The change in orthostatic hypotension was significant in the amitriptyline group with an average systolic BP orthostatic drop of -9 mmHg (p<0.05).(4) A randomized, double-blind study of 16 inpatients with major depressive disorder were treated with either phenelzine or tranylcypromine. Cardiovascular assessments were completed at baseline and after 6 weeks of treatment. After 6 weeks, 5/7 patients (71%) who received phenelzine had a decrease in standing systolic BP greater than 20 mmHg from baseline. Head-up tilt systolic and diastolic BP decreased from baseline in patients on phenelzine (98/61 mmHg v. 127/65 mmHg, respectively; systolic change p=0.02 and diastolic change p=0.02). After 6 weeks, 6/9 patients (67%) who received tranylcypromine had a decrease in standing systolic BP greater than 20 mmHg from baseline. Head-up tilt systolic and diastolic BP decreased from baseline in patients on tranylcypromine (113/71 mmHg v. 133/69 mmHg, respectively; systolic change p=0.09 and diastolic change p=0.07).(5) Selected MAOIs linked to this monograph include: phenelzine and tranylcypromine. Selected antihypertensive agents include: ACE inhibitors, alpha blockers, ARBs, beta blockers, calcium channel blockers, aprocitentan, clonidine, hydralazine, moxonidine, and sparsentan. |
NARDIL, PARNATE, PHENELZINE SULFATE, TRANYLCYPROMINE SULFATE |
| Lacosamide/Beta-Blockers; Diltiazem; Verapamil SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Lacosamide may enhance the slow inactivation of voltage-gated sodium channels and may cause dose-dependent bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1) CLINICAL EFFECTS: Concurrent use of lacosamide and agents that affect cardiac conduction (beta-blockers, non-dihydropyridine calcium channel blockers) may increase the risk of bradycardia, prolongation of the PR interval, atrioventricular (AV) block, or ventricular tachyarrhythmia.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Lacosamide should be used with caution in patients on concomitant medications that affect cardiac conduction, including beta-blockers and non-dihydropyridine calcium channel blockers.(1) If concurrent use is needed, obtain an ECG before lacosamide therapy and after lacosamide dose is titrated to steady-state.(1) Patients should be monitored closely when lacosamide is given intravenously.(1) DISCUSSION: In a clinical trial in patients with partial-onset seizures, asymptomatic first-degree atrioventricular (AV) block occurred in 4/944 (0.4%) of patient who received lacosamide compared to 0/364 (0%) with placebo.(1) In a clinical trial in patients with diabetic neuropathy, asymptomatic first-degree AV block occurred in 5/1023 (0.5%) of patients who received lacosamide compared to 0/291 (0%) with placebo.(1) Second-degree and complete AV block have been reported in patients with seizures.(1) One case of profound bradycardia was observed in a patient during a 15-minute infusion of 150 mg of lacosamide.(1) Two postmarketing reports of third-degree AV block in patients with significant cardiac history and also receiving metoprolol and amlodipine during infusion of lacosamide injection at doses higher than recommended have been reported.(1) A case report of an 88 year old female taking bisoprolol documented complete AV block after initiation of lacosamide. The patient required pacemaker implementation.(2) |
LACOSAMIDE, MOTPOLY XR, VIMPAT |
| Anticholinesterases/Beta-Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Anticholinesterases inhibit plasma cholinesterases and increase cholinergic activity. Use of anticholinesterases may have vagotonic effects on heart rate (e.g. bradycardia). Concurrent use of anticholinesterases and beta-blockers may have additive effects on bradycardia.(1) CLINICAL EFFECTS: Concurrent use of anticholinesterases and beta-blockers may have additive effects on bradycardia.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of anticholinesterases and beta-blockers is not recommended. Additive effects may be increased with cardioselective beta-blockers (e.g. atenolol). Monitor patients closely if concurrent use is warranted.(1) DISCUSSION: Concurrent use of anticholinesterases and beta-blockers may have additive effects on cardiac conduction and increase the risk of bradycardia.(1) A case report of a 65 year old African American female had a witnessed a presyncopal episode followed by a true syncopal episode with concurrent use of rivastigmine and atenolol. On day 2 of the hospital stay, the patient developed bradycardia with a heart rate in the 40s and sinus pauses greater than 2 seconds. Atenolol was discontinued yet bradycardia persisted. Following discontinuation of rivastigmine, sinus pauses resolved and heart rate returned to normal.(2) A population-based cohort study in Ontario, Canada reviewed the relationship between cholinesterase inhibitor use and syncope-related outcomes over a two year period. Hospital visits for syncope were more frequent in patients receiving cholinesterase inhibitors than controls (31.5 vs 18.6 events per 1000 person-years; adjusted hazard ratio (HR) 1.76; 95% confidence interval (CI) 1.57-1.98). Other syncope-related events were also more common in patients receiving cholinesterase inhibitors than controls: hospital visits for bradycardia (6.9 vs 4.4 events per 1000 person-years; HR 1.69; 95% CI 1.32-2.15); permanent pacemaker insertion (4.7 vs 3.3 events per 1000 person-years; HR 1.49; 95% CI 1.12-2.00); and hip fracture (22.4 vs 19.8 events per 1000 person-years; HR 1.18; 95% CI 1.04-1.34).(3) A population based case-time-control study of 1,009 patients hospitalized for bradycardia within 9 months of using a cholinesterase inhibitor were reviewed for outcomes. Of these patients, 11% required pacemaker insertion during hospitalization and 4% died prior to discharge. With adjustment for temporal changes in drug utilization, hospitalization for bradycardia was associated with recent initiation of a cholinesterase inhibitor drug (adjusted odds ratio (OR) 2.13; 95% CI 1.29-3.51). Risk was similar in patients with pre-existing cardiac disease (adjusted OR 2.25; 95% CI 1.18-4.28) and those receiving negative chronotropic drugs (adjusted OR 2.34; 95% CI 1.16-4.71).(4) |
ANTICHOLIUM, BLOXIVERZ, DEMECARIUM BROMIDE, EDROPHONIUM CHLORIDE, EXELON, MESTINON, NEOSTIGMINE METHYLSULFATE, NEOSTIGMINE-STERILE WATER, PREVDUO, PYRIDOSTIGMINE BROMIDE, PYRIDOSTIGMINE BROMIDE ER, REGONOL, RIVASTIGMINE |
| Insulin/Selected Systemic Non-Cardioselective Beta-Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Not fully established. Probably blockade of a variety of beta-adrenergic responses to hypoglycemia. CLINICAL EFFECTS: Diminished response to insulin may occur. Frequency and severity of hypoglycemic episodes may be increased, while warning symptoms of low blood sugar may be masked. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Try to avoid beta-blocker therapy, particularly in diabetics prone to hypoglycemic attacks. One of the cardioselective agents may decrease risk of hypertensive attacks and allow more rapid glucose recovery from hypoglycemia. Patients should be counseled not to rely on tachycardia to diagnose hypoglycemia, since it is masked by beta-blocker therapy. Diaphoresis is unaffected by beta-blockade and can be used by the diabetic to recognize hypoglycemia. DISCUSSION: A class effect of diminished glucose-lowering effects is expected with concurrent use of beta-blockers and insulin. It is prudent to monitor serum glucose closely in patients receiving beta-blocker therapy because symptoms of hypoglycemia may be masked. A double blind, randomized, 12 month study of 39 patients tested the metabolic effects of pindolol (5 mg BID) compared to control group on insulin sensitivity. The patient's insulin sensitivity index decreased 17% when on pindolol treatment compared to placebo (p<0.01). Insulin mediated glucose uptake was significantly lower (p<0.05) with propranolol treatment than with placebo. (1) A study of 26 patients with chronic heart failure showed that carvedilol (average daily dose 27.5 mg/d) caused a significant decrease in fasting insulin levels (17.09 to 10.77 microU/ml, p <0.05) compared to pre-treatment levels. This trial also showed that patients on carvedilol had significantly (p=0.015) lower fasting insulin levels (10.77 microU/ml) compared to the fasting insulin levels (20.72 microU/ml) of patients on bisoprolol treatment (5.9mg/d).(2) |
ADMELOG, ADMELOG SOLOSTAR, AFREZZA, APIDRA, APIDRA SOLOSTAR, BASAGLAR KWIKPEN U-100, BASAGLAR TEMPO PEN U-100, FIASP, FIASP FLEXTOUCH, FIASP PENFILL, FIASP PUMPCART, HUMALOG, HUMALOG JUNIOR KWIKPEN, HUMALOG KWIKPEN U-100, HUMALOG KWIKPEN U-200, HUMALOG MIX 50-50 KWIKPEN, HUMALOG MIX 75-25, HUMALOG MIX 75-25 KWIKPEN, HUMALOG TEMPO PEN U-100, HUMULIN R U-500, HUMULIN R U-500 KWIKPEN, INSULIN ASPART, INSULIN ASPART FLEXPEN, INSULIN ASPART PENFILL, INSULIN ASPART PROT MIX 70-30, INSULIN DEGLUDEC, INSULIN DEGLUDEC PEN (U-100), INSULIN DEGLUDEC PEN (U-200), INSULIN GLARGINE MAX SOLOSTAR, INSULIN GLARGINE SOLOSTAR, INSULIN GLARGINE-YFGN, INSULIN LISPRO, INSULIN LISPRO JUNIOR KWIKPEN, INSULIN LISPRO KWIKPEN U-100, INSULIN LISPRO PROTAMINE MIX, KIRSTY, KIRSTY PEN, LANTUS, LANTUS SOLOSTAR, LYUMJEV, LYUMJEV KWIKPEN U-100, LYUMJEV KWIKPEN U-200, LYUMJEV TEMPO PEN U-100, MERILOG, MERILOG SOLOSTAR, MYXREDLIN, NOVOLOG, NOVOLOG FLEXPEN, NOVOLOG MIX 70-30, NOVOLOG MIX 70-30 FLEXPEN, NOVOLOG PENFILL, REZVOGLAR KWIKPEN, SEMGLEE (YFGN), SEMGLEE (YFGN) PEN, SOLIQUA 100-33, TOUJEO MAX SOLOSTAR, TOUJEO SOLOSTAR, TRESIBA, TRESIBA FLEXTOUCH U-100, TRESIBA FLEXTOUCH U-200, XULTOPHY 100-3.6 |
| Nateglinide; Repaglinide/Slt Non-Cardioselective B-Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Not fully established. Probably blockade of a variety of beta-adrenergic responses to hypoglycemia. CLINICAL EFFECTS: Diminished response to nateglinide and repaglinide may occur. Frequency and severity of hypoglycemic episodes may be increased, while warning symptoms of low blood sugar may be masked. PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Try to avoid beta-blocker therapy, particularly in diabetics prone to hypoglycemic attacks. One of the cardioselective agents may decrease risk of hypertensive attacks and allow more rapid glucose recovery from hypoglycemia. Patients should be counseled not to rely on tachycardia to diagnose hypoglycemia, since it is masked by beta-blocker therapy. Diaphoresis is unaffected by beta-blockade and can be used by the diabetic to recognize hypoglycemia. DISCUSSION: A double blind, randomized, 12 month study of 39 patients tested the metabolic effects of pindolol (5 mg BID) compared to control group on insulin sensitivity. The patient's insulin sensitivity index decreased 17% when on pindolol treatment compared to placebo (p<0.01). Insulin mediated glucose uptake was significantly lower (p<0.05) with propranolol treatment than with placebo. (1) A study of 26 patients with chronic heart failure showed that carvedilol (average daily dose 27.5 mg/d) caused a significant decrease in fasting insulin levels (17.09 to 10.77 microU/ml, p <0.05) compared to pre-treatment levels. This trial also showed that patients on carvedilol had significantly (p=0.015) lower fasting insulin levels (10.77 microU/ml) compared to the fasting insulin levels (20.72 microU/ml) of patients on bisoprolol treatment (5.9mg/d).(2) |
NATEGLINIDE, REPAGLINIDE |
| Apomorphine/Selected Antihypertensives and Vasodilators SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Apomorphine causes dose-dependent decreases in blood pressure. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1) CLINICAL EFFECTS: Concurrent use of antihypertensives and apomorphine may result in orthostatic hypotension with or without dizziness, nausea, or syncope.(1) PREDISPOSING FACTORS: The risk of orthostatic hypotension may be increased during dose escalation of apomorphine and in patients with renal or hepatic impairment.(1) PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. Counsel patients about the risk of orthostatic hypotension.(1) DISCUSSION: Healthy volunteers who took sublingual nitroglycerin (0.4 mg) concomitantly with apomorphine experienced a mean largest decrease in supine systolic blood pressure (SBP) of 9.7 mm Hg and in supine diastolic blood pressure (DBP) of 9.3 mm Hg, and a mean largest decrease in standing SBP and DBP of 14.3 mm Hg and 13.5 mm Hg, respectively. The maximum decrease in SBP and DBP was 65 mm Hg and 43 mm Hg, respectively. When apomorphine was taken alone, the mean largest decrease in supine SBP and DBP was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing SBP and DBP was 6.7 mm Hg and 8.4 mm Hg, respectively.(1) |
APOKYN, APOMORPHINE HCL, ONAPGO |
| Propranolol/Fluvoxamine SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Fluvoxamine may inhibit the metabolism of propranolol by CYP1A2 and CYP2C19.(1,2) CLINICAL EFFECTS: Concurrent use of fluvoxamine and propranolol may result in increased levels of and effects from propranolol.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: The initial dose of propranolol in patients who are on fluvoxamine should be lower in the beginning and titrated more cautiously. Closely monitor patients for adverse effects in patients on concurrent therapy. The dosage of propranolol may need to be adjusted if fluvoxamine is discontinued.(1) DISCUSSION: In a study of healthy volunteers, fluvoxamine 100 mg daily increased the minimum concentration (Cmin) of propranolol 160 mg daily by a mean of five-fold (range: 2-17). Subjects experienced a slight reduction in heart rate and in exercise diastolic pressure.(1) |
FLUVOXAMINE MALEATE, FLUVOXAMINE MALEATE ER |
| Donepezil; Galantamine/Beta-Blockers SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: Anticholinesterases like donepezil and galantamine inhibit plasma cholinesterases and increase cholinergic activity. Use of anticholinesterases may have vagotonic effects on heart rate (e.g. bradycardia). Concurrent use of anticholinesterases and beta-blockers may have additive effects on bradycardia.(1,2) CLINICAL EFFECTS: Concurrent use of donepezil or galantamine with beta-blockers may have additive effects on bradycardia.(1,2) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Concurrent use of anticholinesterases like donepezil or galantamine with beta-blockers is not recommended. Additive effects may be increased with cardioselective beta-blockers (e.g. atenolol). Monitor patients closely if concurrent use is warranted.(1,2) DISCUSSION: Concurrent use of anticholinesterases and beta-blockers may have additive effects on cardiac conduction and increase the risk of bradycardia.(1,2) A case report of a 65 year old African American female had a witnessed a presyncopal episode followed by a true syncopal episode with concurrent use of rivastigmine and atenolol. On day 2 of the hospital stay, the patient developed bradycardia with a heart rate in the 40s and sinus pauses greater than 2 seconds. Atenolol was discontinued yet bradycardia persisted. Following discontinuation of rivastigmine, sinus pauses resolved and heart rate returned to normal.(3) A population-based cohort study in Ontario, Canada reviewed the relationship between cholinesterase inhibitor use and syncope-related outcomes over a two year period. Hospital visits for syncope were more frequent in patients receiving cholinesterase inhibitors than controls (31.5 vs 18.6 events per 1000 person-years; adjusted hazard ratio (HR) 1.76; 95% confidence interval (CI) 1.57-1.98). Other syncope-related events were also more common in patients receiving cholinesterase inhibitors than controls: hospital visits for bradycardia (6.9 vs 4.4 events per 1000 person-years; HR 1.69; 95% CI 1.32-2.15); permanent pacemaker insertion (4.7 vs 3.3 events per 1000 person-years; HR 1.49; 95% CI 1.12-2.00); and hip fracture (22.4 vs 19.8 events per 1000 person-years; HR 1.18; 95% CI 1.04-1.34).(4) A population based case-time-control study of 1,009 patients hospitalized for bradycardia within 9 months of using a cholinesterase inhibitor were reviewed for outcomes. Of these patients, 11% required pacemaker insertion during hospitalization and 4% died prior to discharge. With adjustment for temporal changes in drug utilization, hospitalization for bradycardia was associated with recent initiation of a cholinesterase inhibitor drug (adjusted odds ratio (OR) 2.13; 95% CI 1.29-3.51). Risk was similar in patients with pre-existing cardiac disease (adjusted OR 2.25; 95% CI 1.18-4.28) and those receiving negative chronotropic drugs (adjusted OR 2.34; 95% CI 1.16-4.71).(5) |
ADLARITY, ARICEPT, DONEPEZIL HCL, DONEPEZIL HCL ODT, GALANTAMINE ER, GALANTAMINE HBR, GALANTAMINE HYDROBROMIDE, MEMANTINE HCL-DONEPEZIL HCL ER, NAMZARIC, ZUNVEYL |
| Propranolol/Selected CYP2D6 Inhibitors SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed. MECHANISM OF ACTION: CYP2D6 inhibitors may inhibit the metabolism of propranolol.(1) CLINICAL EFFECTS: Concurrent use of CYP2D6 inhibitors may result in elevated levels of and toxicity from propranolol, including hypotension and bradycardia.(1) PREDISPOSING FACTORS: None determined. PATIENT MANAGEMENT: Monitor patients receiving concurrent therapy with propranolol and CYP2D6 inhibitors. The dosage of propranolol may need to be adjusted.(1) DISCUSSION: In a pharmacokinetic study in 16 healthy volunteers, concurrent use of quinidine 200 mg (a CYP2D6 inhibitor) increased the area-under-curve (AUC) of propranolol by 2.29-fold.(2) In a pharmacokinetic study in 6 healthy subjects, concurrent use of quinidine increased propranolol AUC 2-fold.(3) A retrospective review of concurrent use of propranolol and antidepressants evaluated the risk of hospitalization or emergency room visit within 30 days of concurrent prescription. In patients receiving antidepressants with moderate to strong CYP2D6 inhibitory effects, patient were an increased risk compared to patients receiving no antidepressants (Hazard Ratio (HR) = 1.53; 95% CI 1.03-2.81 vs. HR = 1.24; 95% CI 0.82-1.88).(4) Case reports of bradycardia and cardiac adverse effects have been reported with concurrent use of propranolol and the antidepressants fluoxetine and paroxetine (strong CYP2D6 inhibitors).(5) Strong CYP2D6 inhibitors include: bupropion, dacomitinib, fluoxetine, mavorixafor, and paroxetine. Moderate CYP2D6 inhibitors include: abiraterone, asunaprevir, berotralstat, capivasertib, cinacalcet, duloxetine, eliglustat, escitalopram, lorcaserin, mirabegron, moclobemide, quinine, ranolazine, and rolapitant. Weak CYP2D6 inhibitors include: celecoxib, desvenlafaxine, diphenhydramine, dimenhydrinate, dronabinol, fedratinib, hydroxychloroquine, imatinib, osilodrostat, ranitidine, and sertraline.(6) |
ABIRATERONE ACETATE, ABIRTEGA, AKEEGA, APLENZIN, ASPRUZYO SPRINKLE, AUVELITY, BUPROPION HCL, BUPROPION HCL SR, BUPROPION XL, CELEBREX, CELECOXIB, CERDELGA, CINACALCET HCL, CONSENSI, CONTRAVE, DESVENLAFAXINE ER, DESVENLAFAXINE SUCCINATE ER, DIMENHYDRINATE, DIPHEN, DIPHENHYDRAMINE HCL, DIPHENHYDRAMINE-0.9% NACL, DRIZALMA SPRINKLE, DRONABINOL, DULOXETINE HCL, DULOXICAINE, ELYXYB, ESCITALOPRAM OXALATE, FLUOXETINE DR, FLUOXETINE HCL, FORFIVO XL, GLEEVEC, HYDROXYCHLOROQUINE SULFATE, IMATINIB MESYLATE, IMKELDI, INREBIC, ISTURISA, LEXAPRO, MARINOL, MIRABEGRON ER, MYRBETRIQ, OLANZAPINE-FLUOXETINE HCL, ORLADEYO, PAROXETINE CR, PAROXETINE ER, PAROXETINE HCL, PAROXETINE MESYLATE, PAXIL, PAXIL CR, PLAQUENIL, PRISTIQ, PROZAC, QUALAQUIN, QUININE HCL, QUININE SULFATE, RANOLAZINE ER, SENSIPAR, SERTRALINE HCL, SOVUNA, SYNDROS, TRUQAP, VARUBI, VIZIMPRO, WELLBUTRIN SR, WELLBUTRIN XL, XOLREMDI, YONSA, ZOLOFT, ZYTIGA |
The following contraindication information is available for PROPRANOLOL HCL (propranolol hcl):
Drug contraindication overview.
No enhanced Contraindications information available for this drug.
No enhanced Contraindications information available for this drug.
There are 6 contraindications.
Absolute contraindication.
| Contraindication List |
|---|
| Acute decompensated heart failure |
| Asthma |
| Cardiogenic shock |
| Complete atrioventricular block |
| Second degree atrioventricular heart block |
| Sinus bradycardia |
There are 9 severe contraindications.
Adequate patient monitoring is recommended for safer drug use.
| Severe List |
|---|
| Cerebrovascular anomaly associated with PHACE syndrome |
| Chronic bronchitis |
| Chronic obstructive pulmonary disease |
| Hypotension |
| Myasthenia gravis |
| Pregnancy |
| Pulmonary emphysema |
| Sick sinus syndrome |
| Wolff-parkinson-white pattern |
There are 5 moderate contraindications.
Clinically significant contraindication, where the condition can be managed or treated before the drug may be given safely.
| Moderate List |
|---|
| Diabetes mellitus |
| Disease of liver |
| Hypoglycemic disorder |
| Kidney disease with reduction in glomerular filtration rate (GFr) |
| Tobacco smoker |
The following adverse reaction information is available for PROPRANOLOL HCL (propranolol hcl):
Adverse reaction overview.
No enhanced Common Adverse Effects information available for this drug.
No enhanced Common Adverse Effects information available for this drug.
There are 28 severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
| None. |
Asthma exacerbation Bronchospastic pulmonary disease Chronic heart failure |
| Rare/Very Rare |
|---|
|
Acute cognitive impairment Acute respiratory distress syndrome Agranulocytosis Anaphylaxis Bradycardia Cardiac arrest Cardiac arrhythmia Erythema multiforme Exfoliative dermatitis Hallucinations Heart block Hypotension Idiopathic thrombocytopenic purpura Ischemic colitis Laryngismus Mesenteric artery thrombosis Orthostatic hypotension Peripheral vasoconstriction Peyronie's disease Pharyngitis Psoriasiform eruption Purpura Stevens-johnson syndrome Systemic lupus erythematosus Toxic epidermal necrolysis |
There are 26 less severe adverse reactions.
| More Frequent | Less Frequent |
|---|---|
|
Fatigue General weakness Insomnia |
Abdominal pain with cramps Constipation Depression Diarrhea Dizziness Erectile dysfunction Hypoglycemic disorder Nausea Vomiting |
| Rare/Very Rare |
|---|
|
Alopecia Dream disorder Dry eye Dysgeusia Erythema Fever Lethargy Lupus-like syndrome Mood changes Myopathy Ocular irritation Paresthesia Urticaria Visual changes |
The following precautions are available for PROPRANOLOL HCL (propranolol hcl):
No enhanced Pediatric Use information available for this drug.
Contraindicated
Severe Precaution
Management or Monitoring Precaution
Contraindicated
| None |
Severe Precaution
| None |
Management or Monitoring Precaution
| None |
There are no adequate and well-controlled studies to date using propranolol in pregnant women. Safe use of propranolol during pregnancy has not been established. Low birthweight infants with respiratory distress and hypoglycemia have been born to women who received propranolol throughout pregnancy.
Bradycardia, hypoglycemia, and respiratory depression also have been reported in neonates whose mothers received propranolol at parturition; adequate facilities for monitoring such infants at birth should be available. The manufacturers state that the drug should be used during pregnancy only when the possible benefits outweigh the potential risks to the fetus. Embryotoxicity (reduced litter size, increased resorption rates) and neonatal toxicity (deaths) have been reported in reproductive studies in rats receiving propranolol hydrochloride 150 mg/kg daily by gavage or in the diet throughout pregnancy and lactation; however, such effects were not observed in rats receiving 80 mg/kg daily (equivalent to the maximum recommended human dosage on a mg/m2 basis). No evidence of embryotoxicity or neonatal toxicity was observed in rabbits receiving oral doses of propranolol hydrochloride of up to 150 mg/kg daily (about 5 times the maximum recommended oral human daily dose) throughout pregnancy and lactation.
Bradycardia, hypoglycemia, and respiratory depression also have been reported in neonates whose mothers received propranolol at parturition; adequate facilities for monitoring such infants at birth should be available. The manufacturers state that the drug should be used during pregnancy only when the possible benefits outweigh the potential risks to the fetus. Embryotoxicity (reduced litter size, increased resorption rates) and neonatal toxicity (deaths) have been reported in reproductive studies in rats receiving propranolol hydrochloride 150 mg/kg daily by gavage or in the diet throughout pregnancy and lactation; however, such effects were not observed in rats receiving 80 mg/kg daily (equivalent to the maximum recommended human dosage on a mg/m2 basis). No evidence of embryotoxicity or neonatal toxicity was observed in rabbits receiving oral doses of propranolol hydrochloride of up to 150 mg/kg daily (about 5 times the maximum recommended oral human daily dose) throughout pregnancy and lactation.
Since propranolol is distributed into milk, the drug should be used with caution in nursing women.
No enhanced Geriatric Use information available for this drug.
The following prioritized warning is available for PROPRANOLOL HCL (propranolol hcl):
WARNING: Do not stop using this drug without first consulting your doctor. Your condition may become worse when the drug is suddenly stopped, especially if you have chest pain (angina) or heart disease (such as coronary artery disease, ischemic heart disease, high blood pressure). If your doctor decides you should no longer use this drug, you must gradually decrease your dose according to your doctor's instructions.
When gradually stopping this medication, it is recommended that you temporarily limit physical activity to decrease strain on the heart. Get medical help right away if you develop: worsening chest pain, tightness/pressure in the chest, chest pain spreading to the jaw/neck/arm, unusual sweating, trouble breathing, or fast/irregular heartbeat.
WARNING: Do not stop using this drug without first consulting your doctor. Your condition may become worse when the drug is suddenly stopped, especially if you have chest pain (angina) or heart disease (such as coronary artery disease, ischemic heart disease, high blood pressure). If your doctor decides you should no longer use this drug, you must gradually decrease your dose according to your doctor's instructions.
When gradually stopping this medication, it is recommended that you temporarily limit physical activity to decrease strain on the heart. Get medical help right away if you develop: worsening chest pain, tightness/pressure in the chest, chest pain spreading to the jaw/neck/arm, unusual sweating, trouble breathing, or fast/irregular heartbeat.
The following icd codes are available for PROPRANOLOL HCL (propranolol hcl)'s list of indications:
| Angina | |
| I20 | Angina pectoris |
| I20.0 | Unstable angina |
| I20.1 | Angina pectoris with documented spasm |
| I20.2 | Refractory angina pectoris |
| I20.8 | Other forms of angina pectoris |
| I20.81 | Angina pectoris with coronary microvascular dysfunction |
| I20.89 | Other forms of angina pectoris |
| I20.9 | Angina pectoris, unspecified |
| I23.7 | Postinfarction angina |
| I25.11 | Atherosclerotic heart disease of native coronary artery with angina pectoris |
| I25.110 | Atherosclerotic heart disease of native coronary artery with unstable angina pectoris |
| I25.111 | Atherosclerotic heart disease of native coronary artery with angina pectoris with documented spasm |
| I25.112 | Atherosclerotic heart disease of native coronary artery with refractory angina pectoris |
| I25.118 | Atherosclerotic heart disease of native coronary artery with other forms of angina pectoris |
| I25.119 | Atherosclerotic heart disease of native coronary artery with unspecified angina pectoris |
| I25.7 | Atherosclerosis of coronary artery bypass graft(s) and coronary artery of transplanted heart with angina pectoris |
| I25.70 | Atherosclerosis of coronary artery bypass graft(s), unspecified, with angina pectoris |
| I25.700 | Atherosclerosis of coronary artery bypass graft(s), unspecified, with unstable angina pectoris |
| I25.701 | Atherosclerosis of coronary artery bypass graft(s), unspecified, with angina pectoris with documented spasm |
| I25.702 | Atherosclerosis of coronary artery bypass graft(s), unspecified, with refractory angina pectoris |
| I25.708 | Atherosclerosis of coronary artery bypass graft(s), unspecified, with other forms of angina pectoris |
| I25.709 | Atherosclerosis of coronary artery bypass graft(s), unspecified, with unspecified angina pectoris |
| I25.71 | Atherosclerosis of autologous vein coronary artery bypass graft(s) with angina pectoris |
| I25.710 | Atherosclerosis of autologous vein coronary artery bypass graft(s) with unstable angina pectoris |
| I25.711 | Atherosclerosis of autologous vein coronary artery bypass graft(s) with angina pectoris with documented spasm |
| I25.712 | Atherosclerosis of autologous vein coronary artery bypass graft(s) with refractory angina pectoris |
| I25.718 | Atherosclerosis of autologous vein coronary artery bypass graft(s) with other forms of angina pectoris |
| I25.719 | Atherosclerosis of autologous vein coronary artery bypass graft(s) with unspecified angina pectoris |
| I25.72 | Atherosclerosis of autologous artery coronary artery bypass graft(s) with angina pectoris |
| I25.720 | Atherosclerosis of autologous artery coronary artery bypass graft(s) with unstable angina pectoris |
| I25.721 | Atherosclerosis of autologous artery coronary artery bypass graft(s) with angina pectoris with documented spasm |
| I25.722 | Atherosclerosis of autologous artery coronary artery bypass graft(s) with refractory angina pectoris |
| I25.728 | Atherosclerosis of autologous artery coronary artery bypass graft(s) with other forms of angina pectoris |
| I25.729 | Atherosclerosis of autologous artery coronary artery bypass graft(s) with unspecified angina pectoris |
| I25.73 | Atherosclerosis of nonautologous biological coronary artery bypass graft(s) with angina pectoris |
| I25.730 | Atherosclerosis of nonautologous biological coronary artery bypass graft(s) with unstable angina pectoris |
| I25.731 | Atherosclerosis of nonautologous biological coronary artery bypass graft(s) with angina pectoris with documented spasm |
| I25.732 | Atherosclerosis of nonautologous biological coronary artery bypass graft(s) with refractory angina pectoris |
| I25.738 | Atherosclerosis of nonautologous biological coronary artery bypass graft(s) with other forms of angina pectoris |
| I25.739 | Atherosclerosis of nonautologous biological coronary artery bypass graft(s) with unspecified angina pectoris |
| I25.75 | Atherosclerosis of native coronary artery of transplanted heart with angina pectoris |
| I25.750 | Atherosclerosis of native coronary artery of transplanted heart with unstable angina |
| I25.751 | Atherosclerosis of native coronary artery of transplanted heart with angina pectoris with documented spasm |
| I25.752 | Atherosclerosis of native coronary artery of transplanted heart with refractory angina pectoris |
| I25.758 | Atherosclerosis of native coronary artery of transplanted heart with other forms of angina pectoris |
| I25.759 | Atherosclerosis of native coronary artery of transplanted heart with unspecified angina pectoris |
| I25.76 | Atherosclerosis of bypass graft of coronary artery of transplanted heart with angina pectoris |
| I25.760 | Atherosclerosis of bypass graft of coronary artery of transplanted heart with unstable angina |
| I25.761 | Atherosclerosis of bypass graft of coronary artery of transplanted heart with angina pectoris with documented spasm |
| I25.762 | Atherosclerosis of bypass graft of coronary artery of transplanted heart with refractory angina pectoris |
| I25.768 | Atherosclerosis of bypass graft of coronary artery of transplanted heart with other forms of angina pectoris |
| I25.769 | Atherosclerosis of bypass graft of coronary artery of transplanted heart with unspecified angina pectoris |
| I25.79 | Atherosclerosis of other coronary artery bypass graft(s) with angina pectoris |
| I25.790 | Atherosclerosis of other coronary artery bypass graft(s) with unstable angina pectoris |
| I25.791 | Atherosclerosis of other coronary artery bypass graft(s) with angina pectoris with documented spasm |
| I25.792 | Atherosclerosis of other coronary artery bypass graft(s) with refractory angina pectoris |
| I25.798 | Atherosclerosis of other coronary artery bypass graft(s) with other forms of angina pectoris |
| I25.799 | Atherosclerosis of other coronary artery bypass graft(s) with unspecified angina pectoris |
| Essential tremor | |
| G25.0 | Essential tremor |
| Hypertension | |
| I10 | Essential (primary) hypertension |
| I11 | Hypertensive heart disease |
| I11.0 | Hypertensive heart disease with heart failure |
| I11.9 | Hypertensive heart disease without heart failure |
| I12 | Hypertensive chronic kidney disease |
| I12.0 | Hypertensive chronic kidney disease with stage 5 chronic kidney disease or end stage renal disease |
| I12.9 | Hypertensive chronic kidney disease with stage 1 through stage 4 chronic kidney disease, or unspecified chronic kidney disease |
| I13 | Hypertensive heart and chronic kidney disease |
| I13.0 | Hypertensive heart and chronic kidney disease with heart failure and stage 1 through stage 4 chronic kidney disease, or unspecified chronic kidney disease |
| I13.1 | Hypertensive heart and chronic kidney disease without heart failure |
| I13.10 | Hypertensive heart and chronic kidney disease without heart failure, with stage 1 through stage 4 chronic kidney disease, or unspecified chronic kidney disease |
| I13.11 | Hypertensive heart and chronic kidney disease without heart failure, with stage 5 chronic kidney disease, or end stage renal disease |
| I13.2 | Hypertensive heart and chronic kidney disease with heart failure and with stage 5 chronic kidney disease, or end stage renal disease |
| I15.1 | Hypertension secondary to other renal disorders |
| Hypertrophic cardiomyopathy | |
| I42.1 | Obstructive hypertrophic cardiomyopathy |
| I42.2 | Other hypertrophic cardiomyopathy |
| Migraine prevention | |
| G43 | Migraine |
| G43.0 | Migraine without aura |
| G43.00 | Migraine without aura, not intractable |
| G43.001 | Migraine without aura, not intractable, with status migrainosus |
| G43.009 | Migraine without aura, not intractable, without status migrainosus |
| G43.01 | Migraine without aura, intractable |
| G43.011 | Migraine without aura, intractable, with status migrainosus |
| G43.019 | Migraine without aura, intractable, without status migrainosus |
| G43.1 | Migraine with aura |
| G43.10 | Migraine with aura, not intractable |
| G43.101 | Migraine with aura, not intractable, with status migrainosus |
| G43.109 | Migraine with aura, not intractable, without status migrainosus |
| G43.11 | Migraine with aura, intractable |
| G43.111 | Migraine with aura, intractable, with status migrainosus |
| G43.119 | Migraine with aura, intractable, without status migrainosus |
| G43.4 | Hemiplegic migraine |
| G43.40 | Hemiplegic migraine, not intractable |
| G43.401 | Hemiplegic migraine, not intractable, with status migrainosus |
| G43.409 | Hemiplegic migraine, not intractable, without status migrainosus |
| G43.41 | Hemiplegic migraine, intractable |
| G43.411 | Hemiplegic migraine, intractable, with status migrainosus |
| G43.419 | Hemiplegic migraine, intractable, without status migrainosus |
| G43.5 | Persistent migraine aura without cerebral infarction |
| G43.50 | Persistent migraine aura without cerebral infarction, not intractable |
| G43.501 | Persistent migraine aura without cerebral infarction, not intractable, with status migrainosus |
| G43.509 | Persistent migraine aura without cerebral infarction, not intractable, without status migrainosus |
| G43.51 | Persistent migraine aura without cerebral infarction, intractable |
| G43.511 | Persistent migraine aura without cerebral infarction, intractable, with status migrainosus |
| G43.519 | Persistent migraine aura without cerebral infarction, intractable, without status migrainosus |
| G43.6 | Persistent migraine aura with cerebral infarction |
| G43.60 | Persistent migraine aura with cerebral infarction, not intractable |
| G43.601 | Persistent migraine aura with cerebral infarction, not intractable, with status migrainosus |
| G43.609 | Persistent migraine aura with cerebral infarction, not intractable, without status migrainosus |
| G43.61 | Persistent migraine aura with cerebral infarction, intractable |
| G43.611 | Persistent migraine aura with cerebral infarction, intractable, with status migrainosus |
| G43.619 | Persistent migraine aura with cerebral infarction, intractable, without status migrainosus |
| G43.7 | Chronic migraine without aura |
| G43.70 | Chronic migraine without aura, not intractable |
| G43.701 | Chronic migraine without aura, not intractable, with status migrainosus |
| G43.709 | Chronic migraine without aura, not intractable, without status migrainosus |
| G43.71 | Chronic migraine without aura, intractable |
| G43.711 | Chronic migraine without aura, intractable, with status migrainosus |
| G43.719 | Chronic migraine without aura, intractable, without status migrainosus |
| G43.8 | Other migraine |
| G43.80 | Other migraine, not intractable |
| G43.801 | Other migraine, not intractable, with status migrainosus |
| G43.809 | Other migraine, not intractable, without status migrainosus |
| G43.81 | Other migraine, intractable |
| G43.811 | Other migraine, intractable, with status migrainosus |
| G43.819 | Other migraine, intractable, without status migrainosus |
| G43.82 | Menstrual migraine, not intractable |
| G43.821 | Menstrual migraine, not intractable, with status migrainosus |
| G43.829 | Menstrual migraine, not intractable, without status migrainosus |
| G43.83 | Menstrual migraine, intractable |
| G43.831 | Menstrual migraine, intractable, with status migrainosus |
| G43.839 | Menstrual migraine, intractable, without status migrainosus |
| G43.9 | Migraine, unspecified |
| G43.90 | Migraine, unspecified, not intractable |
| G43.901 | Migraine, unspecified, not intractable, with status migrainosus |
| G43.909 | Migraine, unspecified, not intractable, without status migrainosus |
| G43.91 | Migraine, unspecified, intractable |
| G43.911 | Migraine, unspecified, intractable, with status migrainosus |
| G43.919 | Migraine, unspecified, intractable, without status migrainosus |
| G43.B | Ophthalmoplegic migraine |
| G43.B0 | Ophthalmoplegic migraine, not intractable |
| G43.B1 | Ophthalmoplegic migraine, intractable |
| G43.C | Periodic headache syndromes in child or adult |
| G43.C0 | Periodic headache syndromes in child or adult, not intractable |
| G43.C1 | Periodic headache syndromes in child or adult, intractable |
| G43.D | Abdominal migraine |
| G43.D0 | Abdominal migraine, not intractable |
| G43.D1 | Abdominal migraine, intractable |
| G43.E | Chronic migraine with aura |
| G43.E0 | Chronic migraine with aura, not intractable |
| G43.E01 | Chronic migraine with aura, not intractable, with status migrainosus |
| G43.E09 | Chronic migraine with aura, not intractable, without status migrainosus |
| G43.E1 | Chronic migraine with aura, intractable |
| G43.E11 | Chronic migraine with aura, intractable, with status migrainosus |
| G43.E19 | Chronic migraine with aura, intractable, without status migrainosus |
| Myocardial reinfarction prevention | |
| I21 | Acute myocardial infarction |
| I21.0 | ST elevation (STEMi) myocardial infarction of anterior wall |
| I21.01 | ST elevation (STEMi) myocardial infarction involving left main coronary artery |
| I21.02 | ST elevation (STEMi) myocardial infarction involving left anterior descending coronary artery |
| I21.09 | ST elevation (STEMi) myocardial infarction involving other coronary artery of anterior wall |
| I21.1 | ST elevation (STEMi) myocardial infarction of inferior wall |
| I21.11 | ST elevation (STEMi) myocardial infarction involving right coronary artery |
| I21.19 | ST elevation (STEMi) myocardial infarction involving other coronary artery of inferior wall |
| I21.2 | ST elevation (STEMi) myocardial infarction of other sites |
| I21.21 | ST elevation (STEMi) myocardial infarction involving left circumflex coronary artery |
| I21.29 | ST elevation (STEMi) myocardial infarction involving other sites |
| I21.3 | ST elevation (STEMi) myocardial infarction of unspecified site |
| I21.4 | Non-ST elevation (NSTEMi) myocardial infarction |
| I21.9 | Acute myocardial infarction, unspecified |
| I21.A | Other type of myocardial infarction |
| I21.A1 | Myocardial infarction type 2 |
| I21.A9 | Other myocardial infarction type |
| I21.B | Myocardial infarction with coronary microvascular dysfunction |
| I22 | Subsequent ST elevation (STEMi) and non-ST elevation (NSTEMi) myocardial infarction |
| I22.0 | Subsequent ST elevation (STEMi) myocardial infarction of anterior wall |
| I22.1 | Subsequent ST elevation (STEMi) myocardial infarction of inferior wall |
| I22.2 | Subsequent non-ST elevation (NSTEMi) myocardial infarction |
| I22.8 | Subsequent ST elevation (STEMi) myocardial infarction of other sites |
| I22.9 | Subsequent ST elevation (STEMi) myocardial infarction of unspecified site |
| I25.2 | Old myocardial infarction |
| I25.85 | Chronic coronary microvascular dysfunction |
| Pheochromocytoma adjunct therapy | |
| C74.1 | Malignant neoplasm of medulla of adrenal gland |
| C74.10 | Malignant neoplasm of medulla of unspecified adrenal gland |
| C74.11 | Malignant neoplasm of medulla of right adrenal gland |
| C74.12 | Malignant neoplasm of medulla of left adrenal gland |
| D35.0 | Benign neoplasm of adrenal gland |
| D35.00 | Benign neoplasm of unspecified adrenal gland |
| D35.01 | Benign neoplasm of right adrenal gland |
| D35.02 | Benign neoplasm of left adrenal gland |
| E31.22 | Multiple endocrine neoplasia [MEn] type IIA |
| E31.23 | Multiple endocrine neoplasia [MEn] type IIB |
| Ventricular rate control in atrial fibrillation | |
| I48.0 | Paroxysmal atrial fibrillation |
| I48.1 | Persistent atrial fibrillation |
| I48.11 | Longstanding persistent atrial fibrillation |
| I48.2 | Chronic atrial fibrillation |
| I48.20 | Chronic atrial fibrillation, unspecified |
| I48.21 | Permanent atrial fibrillation |
| I48.91 | Unspecified atrial fibrillation |
Formulary Reference Tool