Carvedilol Er (carvedilol phosphate)

Patients whose conditions are controlled with immediate-release carvedilol tablets alone or in combination with other drugs may be switched to carvedilol phosphate extended-release capsules. Patients who are receiving a daily carvedilol dosage of 6.25 (3.125 mg twice daily), 12.5 (6.25 mg twice daily), 25 (12.5 mg twice daily), or 50 mg (25 mg twice daily) as immediate-release tablets may be switched to a dosage of 10, 20, 40, or 80 mg once daily, respectively, as carvedilol phosphate extended-release capsules. Subsequent titration to higher or lower dosages may be necessary and should be guided by the patient's clinical response.

Carvedilol and carvedilol phosphate are administered orally. Food has little, if any, effect on the oral bioavailability of carvedilol immediate-release tablets but may decrease the rate of absorption, resulting in reduced and delayed peak plasma concentrations. Therefore, to potentially decrease the risk of orthostatic hypotension, it is recommended that carvedilol be administered with food. In addition, the manufacturer suggests that manifestations of vasodilation in patients receiving concomitant therapy with an angiotensin-converting enzyme (ACE) inhibitor may be reduced by administering carvedilol 2 hours prior to the latter drug.

Food increases the bioavailability of carvedilol phosphate extended-release capsules and the manufacturer states that the extended-release capsules should be taken with food. Carvedilol extended-release capsules should be taken once daily in the morning and should be swallowed whole; the capsule and/or its contents should not be crushed, chewed, or taken in divided doses. However, carvedilol extended-release capsules may be opened carefully and the entire contents sprinkled over a spoonful of applesauce, immediately prior to administration. The applesauce should not be warm, and the drug and applesauce mixture should be consumed in entirety. The drug and applesauce mixture should not be stored for future use. The absorption of the beads sprinkled on foods other than applesauce has not been studied.

Metabolized by cytochrome P-450 (CYP) isoenzymes, principally CYP2D6 and CYP2C9; also metabolized to a lesser extent by CYP3A4, CYP2C19, CYP1A2, CYP2E1.

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

Beta-Blockers/Arbutamine

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Beta-Blockers/Fenoldopam

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

P-Glycoprotein (P-GP) Inh/Colchicine (FOR CARDIOPROTECTION)

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: P-glycoprotein (P-gp) inhibitors may affect the transport of colchicine, a P-gp substrate.(1,2)

CLINICAL EFFECTS: Concurrent use of a P-gp inhibitor may result in elevated levels of and toxicity from colchicine. Symptoms of colchicine toxicity include abdominal pain; nausea or vomiting; severe diarrhea; muscle weakness or pain; numbness or tingling in the fingers or toes; myelosuppression; feeling weak or tired; increased infections; and pale or gray color of the lips, tongue, or palms of hands.(1,2)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with renal or hepatic impairment.(1,2)

PATIENT MANAGEMENT: The manufacturer of colchicine used for cardiovascular risk reduction states that concurrent use of colchicine with P-gp inhibitors is contraindicated.(1)

DISCUSSION: There are several reports of colchicine toxicity(3-5) and death(6,7) following the addition of clarithromycin to therapy. In a retrospective review of 116 patients who received clarithromycin and colchicine during the same hospitalization, 10.2% (9/88) of patients who received simultaneous therapy died, compared to 3.6% (1/28) of patients who received sequential therapy.(8) An FDA review of 117 colchicine-related deaths that were not attributable to overdose found that 60 deaths (51%) involved concurrent use of clarithromycin.(2) There is one case report of colchicine toxicity with concurrent erythromycin.(9) In a study in 20 subjects, pretreatment with diltiazem (240 mg daily for 7 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by 44.2% (range -46.6% to 318.3%) and by 93.4% (range -30.2% to 338.6%), respectively.(1) In a study in 24 subjects, pretreatment with verapamil (240 mg twice daily for 7 days) increased the Cmax and AUC of a single dose of colchicine (0.6 mg) by 40.1% (range -47.1% to 149.5%) and by 103.3% (range -9.8% to 217.2%), respectively.(1) Colchicine toxicity has been reported with concurrent use of CYP3A4 and P-gp inhibitors such as clarithromycin, cyclosporine, diltiazem, erythromycin, and verapamil.(1,2) P-gp inhibitors include abrocitinib, amiodarone, asciminib, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, cyclosporine, danicopan, daraxonrasib, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, erythromycin, flibanserin, fluvoxamine, fostamatinib, glecaprevir/pibrentasvir, imlunestrant, ivacaftor, lapatinib, ledipasvir, mavorixafor, neratinib, osimertinib, pirtobrutinib, propafenone, quinidine, ranolazine, schisandra, selpercatinib, sotorasib, tepotinib, valbenazine, velpatasvir, vemurafenib, venetoclax, vepdegestrant, verapamil, vimseltinib, and voclosporin.(1,10,11)

P-Glycoprotein (P-GP) Inhibitors/Oral Lefamulin

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 P-glycoprotein (P-gp) may increase the absorption of lefamulin.(1) Oral lefamulin tablets may inhibit the metabolism of P-gp inhibitors that are also sensitive CYP3A4 substrates (i.e., asunaprevir, felodipine, ivacaftor, and neratinib).(1-3)

CLINICAL EFFECTS: The concurrent administration of lefamulin with an inhibitor of P-gp may result in elevated levels of lefamulin and signs of toxicity, such as QT prolongation. Coadministration of oral lefamulin with agents that are also sensitive CYP3A4 substrates (i.e., asunaprevir, felodipine, ivacaftor, and neratinib) may result in elevated levels and toxicities of the sensitive CYP3A4 substrate.

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade 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 concentrations of either QT prolonging drug are additional risk factors for torsade 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 US manufacturer of lefamulin states that oral lefamulin tablet coadministration with P-gp inhibitors should be avoided.(1) If concomitant therapy with a P-gp inhibitor is necessary, monitor patients closely for prolongation of the QT interval. Obtain serum calcium, magnesium, and potassium levels and monitor ECG at regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. Concomitant use of asunaprevir, felodipine, ivacaftor, or neratinib requires close monitoring for adverse effects of these drugs.(1) The manufacturer of venetoclax states that if concurrent use with a P-gp substrate cannot be avoided, take lefamulin at least 6 hours before venetoclax.(5)

DISCUSSION: Coadministration of ketoconazole (a strong CYP3A4 and P-gp inhibitor) with lefamulin tablets increased lefamulin area-under-the-curve (AUC) and maximum concentration (Cmax) by 165% and 58%.(1) In a study, oral lefamulin tablets administered concomitantly with and at 2 or 4 hours before oral midazolam (a CYP3A4 substrate) increased the area-under-curve (AUC) and maximum concentration (Cmax) of midazolam by 200% and 100%, respectively. No clinically significant effect on midazolam pharmacokinetics was observed when co-administered with lefamulin injection.(1) P-gp inhibitors include: asunaprevir, belumosudil, capmatinib, carvedilol, cimetidine, danicopan, daridorexant, diosmin, flibanserin, fluvoxamine, fostamatinib, ginseng, glecaprevir/pibrentasvir, hydroquinidine, ivacaftor, ledipasvir, neratinib, pirtobrutinib, propafenone, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, valbenazine, vimseltinib, and voclosporin.(1-3)

P-Glycoprotein (P-GP) Inhibitors/Topotecan

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 P-glycoprotein may increase the absorption of topotecan.(1)

CLINICAL EFFECTS: The concurrent administration of topotecan with an inhibitor of P-glycoprotein may result in elevated levels of topotecan and signs of toxicity. These signs may include but are not limited to anemia, diarrhea, and thrombocytopenia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of topotecan states that the use of topotecan and P-glycoprotein inhibitors should be avoided. If concurrent use is warranted, carefully monitor patients for adverse effects.(1) For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(2)

DISCUSSION: In clinical studies, the combined use of elacridar (100 mg to 1000 mg) increased the area-under-curve (AUC) of topotecan approximately 2.5-fold.(1) Oral cyclosporine (15 mg/kg) increased the AUC of topotecan lactone and total topotecan to 2-fold to 3-fold of the control group, respectively.(1) P-gp inhibitors linked to this monograph include: adagrasib, amiodarone, asciminib, asunaprevir, aumolertinib, azithromycin, belumosudil, bosutinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan, daraxonrasib, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, erythromycin, flibanserin, ginseng, hydroquinidine, imlunestrant, isavuconazonium, itraconazole, ivacaftor, josamycin, ketoconazole, ledipasvir, lonafarnib, mavorixafor, neratinib, osimertinib, pibrentasvir/glecaprevir, posaconazole, propafenone, quinidine, ranolazine, selpercatinib, sotorasib, tepotinib, tucatinib, valbenazine, velpatasvir, vemurafenib, vepdegestrant, verapamil, vimseltinib, and voclosporin.(3,4)

P-Gp Inhibitors/Daraxonrasib (>150 MG)

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: Daraxonrasib is a substrate of P-gp. P-gp inhibitors may inhibit the metabolism of daraxonrasib.(1)

CLINICAL EFFECTS: Concurrent use of P-gp inhibitors may increase the levels and toxicities of daraxonrasib, including dermatologic toxicity, stomatitis, GI perforation, and interstitial lung disease/pneumonitis.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: For patients taking agents that are P-gp inhibitors, reduce the dose of daraxonrasib to 150 mg daily. After the P-gp inhibitor has been discontinued, resume the daraxonrasib dosage taken prior to initiating the inhibitor.(1)

DISCUSSION: In a pharmacokinetic model, quinidine 300 mg three times daily (a P-gp inhibitor) increased the area under curve (AUC) of daraxonrasib by 1.8-fold.(1) P-gp inhibitors include: abrocitinib, amiodarone, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, curcumin, danicopan, daridorexant, diosmin, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, imlunestrant, ivacaftor, lapatinib, neratinib, osimertinib, pirtobrutinib, propafenone, ranolazine, selpercatinib, tepotinib, tezacaftor, turmeric, valbenazine, velpatasvir, vemurafenib, vepdegestrant, vimseltinib, and voclosporin.(2-3)

P-Gp Or Bcrp Inhibitors/Ubrogepant (> 50 MG)

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 P-glycoprotein (P-gp) or BCRP may increase the absorption of ubrogepant.(1)

CLINICAL EFFECTS: The concurrent administration of ubrogepant with an inhibitor of P-glycoprotein or BCRP may result in elevated levels of ubrogepant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when coadministered with P-gp or BCRP inhibitors. The dose of ubrogepant should not exceed 50 mg for initial dose. If a second dose of ubrogepant is needed, the dose should not exceed 50 mg.(1) For patients on concurrent therapy with vimseltinib and ubrogepant: the manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to ubrogepant.(3) For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(4)

DISCUSSION: Ubrogepant is a substrate of P-gp and BCRP transporters. Use of P-gp or BCRP inhibitors may increase the exposure of ubrogepant. Clinical drug interaction studies with inhibitors of these transporters were not conducted. The US manufacturer of ubrogepant recommends dose adjustment if ubrogepant is coadministered with P-gp or BCRP inhibitors.(1) BCRP inhibitors linked to this monograph include: belumosudil, clopidogrel, curcumin, eltrombopag, febuxostat, fostemsavir, leniolisib, momelotinib, oteseconazole, regorafenib, resmetirom, ritonavir, rolapitant, roxadustat, tafamidis, oral tedizolid, turmeric, vadadustat, and zongertinib.(2,3,5) P-glycoprotein inhibitors linked to this monograph include: asunaprevir, belumosudil, capmatinib, carvedilol, danicopan, daraxonrasib, daridorexant, imlunestrant, neratinib, osimertinib, propafenone, quinidine, selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, valbenazine, vimseltinib, and voclosporin.(2,3,5)

Select P-Gp Inhibitors/Aumolertinib

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: Aumolertinib is a substrate for P-glycoprotein (P-gp). Inhibitors of P-gp may increase intestinal absorption and decrease elimination of aumolertinib.(1)

CLINICAL EFFECTS: Concurrent use with selected P-gp inhibitors may result in higher systemic concentrations of aumolertinib which may increase the risk for cardiac failure, rhabdomyolysis, thrombosis, elevated LFTs, hyponatremia, hematologic toxicity, and QT prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsade de pointes (TdP).(1)

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.(2) 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) Patients with risk factors for thrombosis may be at higher risk of adverse events, including those with advanced age, obesity (BMI >30), smoking, prolonged immobilization, heart failure, hypercoagulable state, history of venous thromboembolism, malignancy, and major surgery. The risk for rhabdomyolysis may be greater in patients 65 years and older, inadequately treated hypothyroidism, renal impairment, carnitine deficiency, malignant hyperthermia, or in patients with a history of rhabdomyolysis.

PATIENT MANAGEMENT: The manufacturer of aumolertinib states concomitant administration of aumolertinib should be avoided with P-gp inhibitors.(1) If concurrent therapy is warranted, 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: Based on in vitro data, aumolertinib is a substrate of P-gp.(1) P-gp inhibitors linked to this interaction are: abrocitinib, asunaprevir, belumosudil, capmatinib, carvedilol, cimetidine, cobicistat, conivaptan, curcumin, cyclosporine, danicopan, daridorexant, diltiazem, diosmin, flibanserin, fluvoxamine, fostamatinib, ginseng, glecaprevir/pibrentasvir, grapefruit, imlunestrant, indinavir, isavuconazole, itraconazole, ivacaftor, josamycin, ketoconazole, mifepristone, neratinib, nirmatrelvir, pirtobrutinib, ritonavir, telaprevir, tepotinib, tezacaftor, tipranavir, tucatinib, valbenazine, velpatasvir, verapamil, vimseltinib, voclosporin, and voxilaprevir.(3)

Selected Inhibitors Of P-Gp Or Bcrp/Pazopanib

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 P-glycoprotein (P-gp) or BCRP may increase the absorption of pazopanib.(1)

CLINICAL EFFECTS: The concurrent administration of pazopanib with an inhibitor of P-glycoprotein or BCRP may result in elevated levels of pazopanib and signs of toxicity.(1)

PREDISPOSING FACTORS: The risk of QT prolongation or torsade de pointes may be increased in patients with cardiovascular disease (e.g. heart failure, myocardial infarction, history of torsade de pointes, congenital long QT syndrome), hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, female gender, or advanced age.(2) 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 torsade 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, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The US manufacturer of pazopanib states concurrent use of P-gp inhibitors or BCRP inhibitors should be avoided.(1) Monitor patients for increased side effects from pazopanib. The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(5) If concurrent therapy is warranted, 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: Pazopanib is a substrate of P-gp and BCRP. Inhibitors of these transporters are expected to increase pazopanib levels.(1) BCRP inhibitors linked to this monograph include: asciminib, belumosudil, clopidogrel, cyclosporine, curcumin, darolutamide, eltrombopag, enasidenib, febuxostat, fostemsavir, grazoprevir, lazertinib, leflunomide, leniolisib, momelotinib, oteseconazole, pirtobrutinib, regorafenib, resmetirom, ritonavir, rolapitant, roxadustat, tafamidis, teriflunomide, tolvaptan, turmeric, vadadustat, and zongertinib.(1,3-5) P-glycoprotein inhibitors linked to this monograph include: asunaprevir, belumosudil, capmatinib, carvedilol, cyclosporine, danicopan, daraxonrasib, daridorexant, diltiazem, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, imlunestrant, isavuconazonium, ivacaftor, ledipasvir, neratinib, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, tezacaftor, ticagrelor, valbenazine, verapamil, vimseltinib, and voclosporin.(3,4)

Selected P-Glycoprotein (P-GP) Inhibitors/Ensartinib

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: Ensartinib is a P-glycoprotein (P-gp) substrate. P-gp inhibitors may increase the levels of ensartinib.(1)

CLINICAL EFFECTS: The concurrent administration of a P-glycoprotein (P-gp) inhibitor may result in elevated levels of and toxicity from ensartinib.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of ensartinib states that concurrent use of P-glycoprotein (P-gp) inhibitors should be avoided.(1) The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(4)

DISCUSSION: Ensartinib is a substrate of P-gp. Inhibitors of P-gp may increase toxicity of ensartinib.(1) Inhibitors of P-gp linked to this monograph include: abrocitinib, amiodarone, Asian ginseng (Panax ginseng), asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, cyclosporine, danicopan, daraxonrasib, daridorexant, diosmin, eliglustat, flibanserin, fostamatinib, ginkgo biloba, glecaprevir and pibrentasvir, hydroquinidine, ivacaftor, lapatinib, mavorixafor, milk thistle (Silybum marianum), neratinib, osimertinib, propafenone, quercetin, quinidine, ranolazine, rolapitant, silibinin, silymarin, sotagliflozin, tepotinib, tezacaftor, valbenazine, velpatasvir, vemurafenib, venetoclax, vepdegestrant, vilazodone, vimseltinib, and voclosporin.(2,3)

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

Agents That Affect Catecholamines/Iobenguane I 123

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Agents That Affect Catecholamines/Iobenguane I 131

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Beta-Blockers (NONSELECTIVE)/Methyldopa

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

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

CLINICAL EFFECTS: Severe hypertension.

PREDISPOSING FACTORS: None determined.

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

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

Beta-Blockers/Allergen Immunotherapy

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

MECHANISM OF ACTION: Beta-blockers may mask early signs and symptoms of anaphylaxis, make the treatment of anaphylaxis more difficult, and increase the severity of the reaction.

CLINICAL EFFECTS: Beta-blockers may reduce a patient's ability to survive a systemic allergic reaction to allergen immunotherapy. Signs and symptoms of anaphylaxis may be masked.

PREDISPOSING FACTORS: Concurrent use of epinephrine with beta-blockers may result in hypertension with reflex bradycardia. Epinephrine resistance in patients with anaphylaxis has been reported.

PATIENT MANAGEMENT: Avoid concomitant administration of immunotherapy and beta-blockers if possible. If patients cannot safely discontinue beta-blockers but have a history of moderate to severe sting-induced anaphylaxis, venom immunotherapy is indicated because the risk of anaphylaxis related to a venom sting is greater than the risk of an immunotherapy-related systemic reaction. In patients taking beta-blockers for whom an acceptable alternative is not available, withholding allergen immunotherapy may be the best option. If both drugs are administered, monitor closely for signs and symptoms of anaphylaxis. Use caution when treating anaphylaxis with epinephrine since response may be poor. Epinephrine administration may worsen anaphylaxis because beta-blockers block the beta effects of epinephrine, which results in predomination of alpha effects. The plasma clearance of epinephrine is decreased. Glucagon may help in the treatment of refractory anaphylaxis in patients receiving beta-blockers.

DISCUSSION: In a case report, a patient taking propranolol was administered pollen extract immunotherapy and immediately developed anaphylaxis. Treatment with epinephrine did not improve symptoms and patient was subsequently intubated.(2) In another case report, a patient taking propranolol was given pollen immunotherapy and developed anaphylaxis. Difficulty in maintaining an adequate blood pressure and pulse continued for several hours despite epinephrine and other supportive measures.(3) There are other case reports of patients taking propranolol with venom immunotherapy that were refractory to treatment.(6-7)

Beta-Blockers/Etrasimod

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

MECHANISM OF ACTION: Initiation of etrasimod has caused transient decreases in heart rate and atrioventricular conduction delays after the first dose. The first dose has also been associated with heart block. Beta-blockers further increase the risk for symptomatic bradycardia or heart block.(1)

CLINICAL EFFECTS: The heart rate lowering effect of etrasimod is transient and is usually seen with the first dose. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes.(1)

PREDISPOSING FACTORS: Pre-existing cardiovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, history of torsades de pointes, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to etrasimod initiation, or factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia, bradycardia, female gender, or advanced age) may increase risk for cardiovascular toxicity due to etrasimod. Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The prescribing information states etrasimod therapy can be initiated in patients receiving stable doses of beta blocker therapy. Cardiology consultation is recommended before initiating a beta blocker in a patient receiving stable etrasimod treatment.(1)

DISCUSSION: Initiation of etrasimod may result in a transient decrease in heart rate and AV conduction delays. In two studies, after the first dose of etrasimod 2 mg, ulcerative colitis patients saw a mean decrease from baseline in heart rate of 7.2 bpm at hour 3 in UC-1 an hour 2 in UC-2.(1) In UC-1, bradycardia was reported on Day 1 in 1% of etrasimod patients, 0.3% on Day 2 compared to no patients receiving placebo.In UC-2 and UC-3, bradycardia was reported on Day 1 in 2.9% of etrasimod patients, 0.3% on Day 2 compared to no patients receiving placebo. Patients experiencing bradycardia were generally asymptomatic. The few patients with symptomatic bradycardia reported dizziness that resolved without intervention.(1) Beta-Blockers linked to this monograph are: atenolol, betaxolol, bisoprolol, carvedilol, esmolol, labetalol, landiolol, metoprolol, nadolol, nebivolol, propranolol and timolol.

Beta-Blockers/Ponesimod

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

MECHANISM OF ACTION: Initiation of ponesimod has caused transient decreases in heart rate and atrioventricular conduction delays after the first dose. Decreases in heart rate start within the first hour and maximal decrease in heart rate was seen at approximately 2-4 hours. The first dose has also been associated with heart block. Beta-blockers further increase the risk for symptomatic bradycardia or heart block.(1)

CLINICAL EFFECTS: The heart rate lowering effect of ponesimod is transient and is usually seen with the first dose. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes.(1)

PREDISPOSING FACTORS: Pre-existing cardiovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, history of torsades de pointes, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to siponimod initiation, or factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia, bradycardia, female gender, or advanced age) may increase risk for cardiovascular toxicity due to siponimod. Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The prescribing information states temporary interruption in beta-blocker therapy may be needed before initiation of ponesimod. Beta-blocker therapy can be initiated in patients receiving stable doses of ponesimod.(1) Treatment initiation recommendations include: - Obtain an ECG in all patients to determine whether preexisting conduction abnormalities are present. - In all patients, a dose titration is recommended for initiation of ponesimod treatment to help reduce cardiac effects. - In patients with sinus bradycardia (HR less than 55 bpm), first- or second-degree [Mobitz type I] AV block, or a history of myocardial infarction or heart failure with onset > 6 months prior to initiation, ECG testing and first dose monitoring is recommended. - Since significant bradycardia may be poorly tolerated in patients with history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, or severe untreated sleep apnea, ponesimod is not recommended in these patients. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy. - Use of ponesimod in patients with a history of recurrent syncope or symptomatic bradycardia should be based on an overall benefit-risk assessment. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring. - For patients receiving a stable dose of a beta-blocker, the resting heart rate should be considered before introducing ponesimod treatment. If the resting heart rate is greater than 55 bpm under chronic beta-blocker treatment, ponesimod can be introduced. If resting heart rate is less than or equal to 55 bpm, beta-blocker treatment should be interrupted until the baseline heart-rate is greater than 55 bpm. Treatment with ponesimod can then be initiated and treatment with a beta-blocker can be reinitiated after ponesimod has been up-titrated to the target maintenance dosage. - If a titration dose is missed or if 4 or more consecutive daily doses are missed during maintenance treatment, reinitiate Day 1 of the dose titration and follow titration monitoring recommendations.(1)

DISCUSSION: After the first titration dose of ponesimod the heart rate decrease starts within an hour, and the Day 1 decline is maximal at approximately 2-4 hours. With continued up-titration, further heart rate decreases are seen on subsequent days, with maximal decrease from Day 1-baseline reached on Day 4-5. The highest daily post-dose decrease in absolute hourly mean heart rate is observed on Day 1, with the pulse declining on average 6 bpm. Post-dose declines on the following days are less pronounced. With continued dosing, heart rate starts increasing after Day 6 and reaches placebo levels within 10 days after treatment initiation. In a study, bradycardia occurred in 5.8% of ponesimod-treated patients compared to 1.6% of patients receiving placebo. Patients who experienced bradycardia were generally asymptomatic. Few patients experienced symptoms, including dizziness or fatigue, and these symptoms resolved within 24 hours without intervention.(1) Beta-Blockers linked to this monograph are: atenolol, betaxolol, bisoprolol, carvedilol, esmolol, landiolol, labetalol, metoprolol, nadolol, nebivolol, propranolol and timolol.

Beta-Blockers/Siponimod

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

MECHANISM OF ACTION: Initiation of siponimod has caused transient decreases in heart rate and atrioventricular conduction delays after the first dose. Decreases in heart rate start within the first hour and maximal decrease in heart rate was seen at approximately 3-4 hours. The first dose has also been associated with heart block. Beta-blockers further increase the risk for symptomatic bradycardia or heart block.(1)

CLINICAL EFFECTS: The heart rate lowering effect of siponimod is transient and is usually seen with the first dose. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes.(1)

PREDISPOSING FACTORS: Pre-existing cardiovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, history of torsades de pointes, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to siponimod initiation, or factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia, bradycardia, female gender, or advanced age) may increase risk for cardiovascular toxicity due to siponimod. Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: The prescribing information states temporary interruption in beta-blocker therapy may be needed before initiation of siponimod. Beta-blocker therapy can be initiated in patients receiving stable doses of siponimod.(1) Treatment initiation recommendations include: - Obtain an ECG in all patients to determine whether preexisting conduction abnormalities are present. - In all patients, a dose titration is recommended for initiation of siponimod treatment to help reduce cardiac effects. - In patients with sinus bradycardia (HR less than 55 bpm), first- or second-degree [Mobitz type I] AV block, or a history of myocardial infarction or heart failure with onset > 6 months prior to initiation, ECG testing and first dose monitoring is recommended. - Since significant bradycardia may be poorly tolerated in patients with history of cardiac arrest, cerebrovascular disease, uncontrolled hypertension, or severe untreated sleep apnea, siponimod is not recommended in these patients. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring strategy. - Use of siponimod in patients with a history of recurrent syncope or symptomatic bradycardia should be based on an overall benefit-risk assessment. If treatment is considered, advice from a cardiologist should be sought prior to initiation of treatment in order to determine the most appropriate monitoring. - For patients receiving a stable dose of a beta-blocker, the resting heart rate should be considered before introducing siponimod treatment. If the resting heart rate is greater than 50 bpm under chronic beta-blocker treatment, siponimod can be introduced. If resting heart rate is less than or equal to 50 bpm, beta-blocker treatment should be interrupted until the baseline heart-rate is greater than 50 bpm. Treatment with siponimod can then be initiated and treatment with a beta-blocker can be reinitiated after siponimod has been up-titrated to the target maintenance dosage. - If a titration dose is missed or if 4 or more consecutive daily doses are missed during maintenance treatment, reinitiate Day 1 of the dose titration and follow titration monitoring recommendations.(1)

DISCUSSION: After the first titration dose of siponimod, the heart rate decrease starts within an hour, and the Day 1 decline is maximal at approximately 3-4 hours. With continued up-titration, further heart rate decreases are seen on subsequent days, with maximal decrease from Day 1-baseline reached on Day 5-6. The highest daily post-dose decrease in absolute hourly mean heart rate is observed on Day 1, with the pulse declining on average 5-6 bpm. Post-dose declines on the following days are less pronounced. With continued dosing, heart rate starts increasing after Day 6 and reaches placebo levels within 10 days after treatment initiation. In Study 1, bradycardia occurred in 4.4% of siponimod-treated patients compared to 2.9% of patients receiving placebo. Patients who experienced bradycardia were generally asymptomatic. Few patients experienced symptoms, including dizziness or fatigue, and these symptoms resolved within 24 hours without intervention.(1) Beta-Blockers linked to this monograph are: atenolol, betaxolol, bisoprolol, carvedilol, esmolol, landiolol, labetalol, metoprolol, nadolol, nebivolol, propranolol and timolol.

Beta-Blockers; Av Node Blockers/Fingolimod

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

MECHANISM OF ACTION: Initiation of fingolimod has a negative chronotropic effect leading to a mean decrease in heart rate of 13 beats per minute (bpm) after the first dose. The first dose has also been associated with heart block. Beta-blockers or agents which slow AV node conduction further increase the risk for symptomatic bradycardia or heart block.

CLINICAL EFFECTS: The heart rate lowering effect of fingolimod is biphasic with an initial decrease usually within 6 hours, followed by a second decrease 12 to 24 hours after the first dose. Symptomatic bradycardia and heart block have been observed. Bradycardia may be associated with an increase in the QTc interval, increasing the risk for torsade de pointes. The cause of death in a patient who died within 24 hour after taking the first dose of fingolimod was not conclusive; however a link to fingolimod or a drug interaction with fingolimod could not be ruled out. Beta-Blockers linked to this monograph are: atenolol, betaxolol, bisoprolol, carvedilol, esmolol, landiolol, labetalol, metoprolol, nadolol, nebivolol, propranolol and timolol. AV Node Blocking agents are:digoxin, diltiazem, flecainide, ivabradine, propafenone and verapamil.

PREDISPOSING FACTORS: Pre-existing cardiovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, history of torsades de pointes, or heart block), severe untreated sleep apnea, a prolonged QTc interval prior to fingolimod initiation, or factors associated with QTc prolongation (e.g. hypokalemia, hypomagnesemia, bradycardia, female gender, or advanced age) may increase risk for cardiovascular toxicity due to fingolimod. Concurrent use of more than one drug known to cause QT prolongation or higher systemic concentrations of either QT prolonging drug are additional risk factors for torsades de pointes. Factors which may increase systemic drug concentrations include rapid infusion of an intravenous dose or impaired metabolism or elimination of the drug (e.g. coadministration with an agent which inhibits its metabolism or elimination, genetic impairment in drug metabolism or elimination, and/or renal/hepatic dysfunction).(5)

PATIENT MANAGEMENT: Fingolimod is contraindicated in patients with Class III/IV heart failure or in patients who have experienced myocardial infarction, unstable angina, stroke, transient ischemic attack (TIA) or decompensated heart failure within the past six months.(1) Patients with pre-existing cardiovascular or cerebrovascular disease (e.g. heart failure, ischemic heart disease, history of myocardial infarction, stroke, or heart block), severe untreated sleep apnea, or a prolonged QTc interval prior to fingolimod initiation should receive cardiologist consultation to evaluate the risks of fingolimod therapy. Patients receiving agents linked to this monograph should have their physician evaluate the possibility of a switch to agents which do not slow heart rate or cardiac conduction. If fingolimod is initiated, the patient should stay overnight in a medical facility with continuous ECG monitoring after the first dose. Correct hypokalemia or hypomagnesemia prior to starting fingolimod. US monitoring recommendations in addition to continuous ECG with overnight monitoring: Check blood pressure hourly. If heart rate (HR) is < 45 beats per minute (BPM) or if the ECG shows new onset of second degree or higher AV block at the end of the monitoring period, then monitoring should continue until the finding has resolved. If patient requires treatment for symptomatic bradycardia, the first dose monitoring strategy should be repeated for the second dose of fingolimod. If, within the first two weeks of treatment one or more fingolimod doses is missed, then first dose procedures are recommended upon resumption. If during weeks 3 and 4 of fingolimod treatment dose is interrupted more than 7 days, then first dose procedures are recommended upon resumption. United Kingdom recommendations(3): Obtain a 12-lead ECG prior to initiating fingolimod therapy. Consult a cardiologist for pretreatment risk-benefit assessment if patient has a resting heart rate less than 55 bpm, history of syncope, second degree or greater AV block, sick-sinus syndrome, concurrent therapy with beta-blockers, Class Ia, or Class III antiarrhythmics, heart failure or other significant cardiovascular disease. Perform continuous ECG monitoring, measure blood pressure and heart rate every hour, and perform a 12-lead ECG 6 hours after the first dose. Monitoring should be extended beyond 6 hours if symptomatic bradycardia or new onset of second degree AV block, Mobitz Type II or third degree AV block has occurred at any time during the monitoring period. If heart rate 6 hours after the first dose is less than 40 bpm, has decreased more than 20 bpm compared with baseline, or if a new onset second degree AV block, Mobitz Type I (Wenckebach) persists, then monitoring should also be continued. If fingolimod treatment is discontinued for more than two weeks, the effects on heart rate and conduction could recur. Thus, first dose monitoring precautions should be followed upon reintroduction of fingolimod.

DISCUSSION: After the first dose of fingolimod, heart rate decrease may begin within an hour. Decline is usually maximal at approximately 6 hours followed by a second decrease 12 to 24 hours after the first dose. The second dose may further decrease heart rate, but the magnitude of change is smaller than the first dose. With continued, chronic dosing, heart rate gradually returns to baseline in about one month.(1,2) Diurnal variation in heart rate and response to exercise are not affected by fingolimod treatment.(2) In a manufacturer sponsored study, fingolimod and atenolol 50 mg daily lowered heart rate 15% more than fingolimod alone. However, additional heart rate lowering was not seen with the combination of extended release diltiazem and fingolimod compared with fingolimod alone.(1)

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

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

MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)

DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)

Non-Cardioselective Beta-Blockers/Beta-2 Agonists

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

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

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

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

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

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

Non-Cardioselective Beta-Blockers/Salmeterol

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

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

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

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

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

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

P-Glycoprotein (P-GP) Inhibitors/Bilastine

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

MECHANISM OF ACTION: P-glycoprotein (P-gp) inhibition may increase the absorption of bilastine.(1,2)

CLINICAL EFFECTS: Concurrent use of P-gp inhibitors may result in elevated levels and toxicities from bilastine, including headache and somnolence.(1,2)

PREDISPOSING FACTORS: The interaction magnitude may be greater in patients with moderate to severe renal impairment.

PATIENT MANAGEMENT: The Canadian manufacturer of bilastine states that concomitant use of P-gp inhibitors with bilastine is not recommended. Coadministration should be avoided in patients with moderate or severe renal impairment.(1) The UK manufacturer of bilastine states that coadministration of bilastine and P-gp inhibitors should be avoided in patients with moderate to severe renal impairment.(2) The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(5)

DISCUSSION: In a study, ketoconazole and erythromycin both increased bilastine area-under-curve (AUC) and maximum concentration (Cmax) by 2-fold and 2- to 3-fold, respectively.(1) The UK manufacturer of bilastine states that these changes do not appear to affect the safety of bilastine.(2) P-gp inhibitors linked to this monograph include: amiodarone, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, cyclosporine, daclatasvir, danicopan, daraxonrasib, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, eliglustat, erythromycin, flibanserin, fluvoxamine, fostamatinib, ginkgo, ginseng, glecaprevir/pibrentasvir, hydroquinidine, imlunestrant, istradefylline, ivacaftor, lapatinib, ledipasvir, mavorixafor, neratinib, osimertinib, paroxetine, pirtobrutinib, posaconazole, propafenone, quercetin, quinidine, quinine, ranolazine, sarecycline, schisandra, selpercatinib, simeprevir, sofosbuvir/velpatasvir/voxilaprevir, sotorasib, tepotinib, valbenazine, vemurafenib, vepdegestrant, verapamil, vimseltinib, and voclosporin.(4,5)

P-Glycoprotein (P-GP) Inhibitors/Colchicine (FOR GOUT & FMF)

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

MECHANISM OF ACTION: P-glycoprotein (P-gp) inhibitors may affect the transport of colchicine, a P-gp substrate.(1,2)

CLINICAL EFFECTS: Concurrent use of a P-gp inhibitor may result in elevated levels of and toxicity from colchicine. Symptoms of colchicine toxicity include abdominal pain; nausea or vomiting; severe diarrhea; muscle weakness or pain; numbness or tingling in the fingers or toes; myelosuppression; feeling weak or tired; increased infections; and pale or gray color of the lips, tongue, or palms of hands.(1,2)

PREDISPOSING FACTORS: This interaction is expected to be more severe in patients with renal and/or hepatic impairment(1,2) and in patients who receive concurrent therapy.

PATIENT MANAGEMENT: The concurrent use of colchicine with P-gp inhibitors is contraindicated in patients with renal or hepatic impairment.(1-3) Avoid concurrent use in other patients, if possible.(3) In patients without renal or hepatic impairment who are currently taking or have taken a P-gp inhibitor in the previous 14 days, the dosage of colchicine should be reduced. For gout flares, the recommended dosage is 0.6 mg (1 tablet) for one dose. This dose should be repeated no earlier than in 3 days.(1,2) For gout prophylaxis, if the original dosage was 0.6 mg twice daily, use 0.3 mg daily. If the original dosage was 0.6 mg daily, use 0.3 mg every other day.(3-12) For Familial Mediterranean fever (FMF), the recommended maximum daily dose is 0.6 mg (may be given as 0.3 mg twice a day).(1,2) Patients should be instructed to immediately report any signs of colchicine toxicity, such as abdominal pain, nausea/significant diarrhea, vomiting; muscle weakness/pain; numbness/tingling in fingers/toes; unusual bleeding or bruising, infections, weakness/tiredness, or pale/gray color of the lips/tongue/palms of hands. The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(13)

DISCUSSION: There are several reports of colchicine toxicity(4-6) and death(7,8) following the addition of clarithromycin to therapy. In a retrospective review of 116 patients who received clarithromycin and colchicine during the same hospitalization, 10.2% (9/88) of patients who received simultaneous therapy died, compared to 3.6% (1/28) of patients who received sequential therapy.(9) An FDA review of 117 colchicine-related deaths that were not attributable to overdose found that 60 deaths (51%) involved concurrent use of clarithromycin.(2) There is one case report of colchicine toxicity with concurrent erythromycin.(10) In a study in 20 subjects, pretreatment with diltiazem (240 mg daily for 7 days) increased the maximum concentration (Cmax) and area-under-curve (AUC) of a single dose of colchicine (0.6 mg) by 44.2% (range -46.6% to 318.3%) and by 93.4% (range -30.2% to 338.6%), respectively.(1) In a study in 24 subjects, pretreatment with verapamil (240 mg twice daily for 7 days) increased the Cmax and AUC of a single dose of colchicine (0.6 mg) by 40.1% (range -47.1% to 149.5%) and by 103.3% (range -9.8% to 217.2%), respectively.(1) Colchicine toxicity has been reported with concurrent use of CYP3A4 and P-gp inhibitors such as clarithromycin, cyclosporine, diltiazem, erythromycin, and verapamil.(1,2) P-gp inhibitors include abrocitinib, amiodarone, asciminib, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, danicopan, daraxonrasib, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, erythromycin, flibanserin, fluvoxamine, fostamatinib, glecaprevir/pibrentasvir, imlunestrant, ivacaftor, lapatinib, ledipasvir, mavorixafor, neratinib, osimertinib, pirtobrutinib, propafenone, quinidine, ranolazine, schisandra, selpercatinib, sotorasib, tepotinib, valbenazine, velpatasvir, vemurafenib, venetoclax, vepdegestrant, verapamil, vimseltinib, and voclosporin.(1,11,12)

P-Glycoprotein (P-GP) Inhibitors/Pralsetinib

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

MECHANISM OF ACTION: P-glycoprotein (P-gp) inhibitors may inhibit cellular efflux of pralsetinib.(1)

CLINICAL EFFECTS: Concurrent administration of a P-gp inhibitor may result in elevated levels of and toxicity from pralsetinib, including hemorrhagic events, pneumonitis, hepatotoxicity, hypertension, and QTc prolongation, which may result in potentially life-threatening cardiac arrhythmias like torsades de pointes (TdP).(1-3)

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 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).(4)

PATIENT MANAGEMENT: Coadministration of pralsetinib with a P-gp inhibitor should be avoided.(1) If coadministration with a P-gp inhibitor cannot be avoided, use with caution and reduce the dose of pralsetinib as follows: -If the current dose is 400 mg once daily, decrease the dose to 300 mg daily. -If the current dose is 300 mg once daily, decrease the dose to 200 mg daily. -If the current dose is 200 mg once daily, decrease the dose to 100 mg daily. After the inhibitor is discontinued for three to five half-lives, resume the dose of pralsetinib at the dose taken prior to initiation of the inhibitor.(1) The manufacturer of venetoclax states that if concurrent use with a P-gp substrate cannot be avoided, take pralsetinib at least 6 hours before venetoclax.(5) The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(8) When concurrent therapy is warranted: consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting. If the QTc interval exceeds 500 ms, interrupt pralsetinib therapy until QTc is <470 ms. Resume pralsetinib at the same dose if risk factors that cause QT prolongation an are identified and corrected. If risk factors that cause QT prolongation are not identified, resume pralsetinib at a reduced dose. Permanently discontinue pralsetinib if the patient develops life-threatening arrhythmia.(3)

DISCUSSION: Coadministration of a single dose of cyclosporine 600 mg (a P-gp inhibitor) with a single pralsetinib 200 mg dose increased pralsetinib concentration maximum (Cmax) by 48% and area-under-curve (AUC) by 81%.(1) P-glycoprotein inhibitors linked to this monograph include: asunaprevir, belumosudil, carvedilol, cyclosporine, danicopan, daraxonrasib, daridorexant, deutivacaftor, diosmin, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, ivacaftor, ledipasvir, neratinib, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, valbenazine, venetoclax, vimseltinib, and voclosporin.(6,7)

P-Glycoprotein (P-GP) Inhibitors/Relugolix

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

MECHANISM OF ACTION: Relugolix is a substrate of the intestinal P-glycoprotein (P-gp) efflux transporter. Inhibitors of P-gp may increase the absorption of relugolix.(1)

CLINICAL EFFECTS: The concurrent administration of relugolix with an inhibitor of P-glycoprotein may result in elevated levels of relugolix and adverse effects, including hot flashes, skin flushing, musculoskeletal pain, hyperglycemia, acute renal injury, transaminitis, arrhythmias, and hemorrhage.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of relugolix states that the coadministration of relugolix with P-gp inhibitors should be avoided. If the P-gp inhibitor is to be used short-term, relugolix may be held for up to 2 weeks. If treatment with relugolix is interrupted for longer than 7 days, resume relugolix with a loading dose of 360 mg on the first day, followed by 120 mg once daily.(1) If coadministration with a P-gp inhibitor cannot be avoided, relugolix should be taken at least 6 hours before the P-gp inhibitor. Monitor the patient more frequently for adverse events.(1) For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(2)

DISCUSSION: Coadministration of relugolix with erythromycin (a P-gp and moderate CYP3A4 inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of relugolix by 6.2-fold. Voriconazole (a strong CYP3A4 inhibitor) did not have a clinically significant effect on the pharmacokinetics of relugolix.(1) P-gp inhibitors linked to this monograph include: amiodarone, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan, curcumin, cyclosporine, daclatasvir, danicopan, daraxonrasib, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, eliglustat, erythromycin, flibanserin, fluvoxamine, fostamatinib, ginkgo, ginseng, glecaprevir/pibrentasvir, indinavir, itraconazole, ivacaftor, josamycin, ketoconazole, lapatinib, lonafarnib, mavorixafor, mibefradil, mifepristone, neratinib, osimertinib, paroxetine, pirtobrutinib, posaconazole, propafenone, quinidine, quinine, ranolazine, ritonavir, sarecycline, schisandra, selpercatinib, simeprevir, sotorasib, telaprevir, telithromycin, tepotinib, tucatinib, valbenazine, velpatasvir, vemurafenib, venetoclax, vepdegestrant, verapamil, vimseltinib, and voclosporin.(3,4)

P-Glycoprotein (P-GP) Inhibitors/Vincristine

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

MECHANISM OF ACTION: P-glycoprotein (P-gp) inhibitors may inhibit cellular efflux of vincristine.(1)

CLINICAL EFFECTS: Concurrent administration of a P-gp inhibitor may result in elevated levels of and toxicity from vincristine including myelosuppression, neurologic toxicity, tumor lysis syndrome, hepatotoxicity, constipation, or bowel obstruction.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Avoid the use of P-gp inhibitors in patients undergoing therapy with vincristine.(1) Consider alternatives with no or minimal P-gp inhibition. The manufacturer of vincristine states that concomitant use of P-gp inhibitors should be avoided.(1) The manufacturer of lopinavir/ritonavir states that patients who develop significant hematological or gastrointestinal toxicity on concomitant vincristine should temporarily hold lopinavir/ritonavir, or use alternative medications that do not inhibit CYP3A4 or P-gp.(2) The manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(3)

DISCUSSION: Vincristine is a substrate of P-gp. Inhibitors of P-gp may increase toxicity of vincristine.(1) There are several case reports of neurotoxicity with concurrent administration of vincristine and itraconazole.(4-6) There is a case report of neurotoxicity with concurrent administration of lopinavir-ritonavir with vincristine.(7) In a prospective study in 22 children receiving various chemotherapy with prophylactic itraconazole oral solution (0.5 ml/kg per day), two children receiving vincristine developed non-alcoholic steatohepatitis (NASH) and one child developed syndrome of inappropriate anti-diuretic hormone secretion (SIADH).(8) Inhibitors of P-gp linked to this monograph include: abrocitinib, amiodarone, Asian ginseng (Panax ginseng), asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, cyclosporine, danicopan, daraxonrasib, daridorexant, deutivacaftor, diltiazem, diosmin, dronedarone, elagolix, eliglustat, erythromycin, flibanserin, fluvoxamine, fostamatinib, ginkgo biloba, glecaprevir and pibrentasvir, imlunestrant, isavuconazonium, ivacaftor, lapatinib, mavorixafor, milk thistle (Silybum marianum), neratinib, osimertinib, pirtobrutinib, propafenone, quercetin, quinidine, ranolazine, rolapitant, Schisandra chinensis, selpercatinib, sofosbuvir, sotorasib, tepotinib, valbenazine, velpatasvir, vemurafenib, venetoclax, vepdegestrant, verapamil, vilazodone, vimseltinib, and voclosporin.(9-10)

Selected P-Glycoprotein (P-GP) Inhibitors/Dabigatran

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

MECHANISM OF ACTION: Dabigatran etexilate is a substrate for the P-glycoprotein (P-gp) system. Inhibition of intestinal P-gp leads to increased absorption of dabigatran.(1-3)

CLINICAL EFFECTS: The concurrent use dabigatran with P-gp inhibitors may lead to elevated plasma levels of dabigatran, increasing the risk for bleeding.

PREDISPOSING FACTORS: Factors associated with an increased risk for bleeding include renal impairment, concomitant use of P-gp inhibitors, patient age >74 years, coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight < 50 kg.(1-4)

PATIENT MANAGEMENT: Assess renal function and evaluate patient for other pre-existing risk factors for bleeding prior to initiating concurrent therapy. The US manufacturer of dabigatran states that the concurrent use of dabigatran and P-gp inhibitors should be avoided in atrial fibrillation patients with severe renal impairment (CrCl less than 30 ml/min) and in patients with moderate renal impairment (CrCl less than 50 ml/min) being treated for or undergoing prophylaxis for deep vein thrombosis (DVT) or pulmonary embolism (PE). The interaction with P-gp inhibitors can be minimized by taking dabigatran several hours apart from the P-gp inhibitor dose.(1) The concomitant use of dabigatran with P-gp inhibitors has not been studied in pediatric patients but may increase exposure to dabigatran.(1) While the US manufacturer of dabigatran states that no dosage adjustment is necessary in other patients,(1) the Canadian manufacturer of dabigatran states that concomitant use of strong P-gp inhibitors (e.g., glecaprevir-pibrentasvir) is contraindicated. When dabigatran is used for the prevention of venous thromboembolism (VTE) after total hip or knee replacement concurrently with amiodarone, quinidine, or verapamil, the dose of dabigatran should be reduced from 110 mg twice daily to 150 mg once daily. For patients with CrCl less than 50 ml/min on verapamil, a further dabigatran dose reduction to 75 mg once daily should be considered. Verapamil should be given at least 2 hours after dabigatran to minimize the interaction.(2) The UK manufacturer of dabigatran also states the use of dabigatran with strong P-gp inhibitors (e.g., cyclosporine, glecaprevir-pibrentasvir or itraconazole) is contraindicated. Concurrent use of ritonavir is not recommended. When dabigatran is used in atrial fibrillation patients and for treatment of DVT and PE concurrently with verapamil, the UK manufacturer recommends reducing the dose of dabigatran from 150 mg twice daily to 110 mg twice daily, taken simultaneously with verapamil. When used for VTE prophylaxis after orthopedic surgery concurrently with amiodarone, quinidine, or verapamil, the dabigatran loading dose should be reduced from 110 mg to 75 mg, and the maintenance dose should be reduced from 220 mg daily to 150 mg daily, taken simultaneously with the P-gp inhibitor. For patients with CLcr 30-50 mL/min on concurrent verapamil, consider further lowering the dabigatran dose to 75 mg daily.(3) If concurrent therapy is warranted, monitor patients for signs of blood loss, including decreased hemoglobin and/or hematocrit, fecal occult blood, and/or decreased blood pressure and promptly evaluate patients with any symptoms. Consider regular monitoring of hemoglobin, platelet levels, and/or activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT). 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 manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(10)

DISCUSSION: When dabigatran was co-administered with amiodarone, the extent and rate of absorption of amiodarone and its active metabolite DEA were essentially unchanged. The dabigatran area-under-curve (AUC) and maximum concentration (Cmax) were increased by about 60% and 50%, respectively;(1,2) however, dabigatran clearance was increased by 65%.(1) Pretreatment with quinidine (200 mg every 2 hours to a total dose of 1000 mg) increased the AUC and Cmax of dabigatran by 53% and 56%, respectively.(1,2) Chronic administration of immediate release verapamil one hour prior to dabigatran dose increased dabigatran AUC by 154%.(4) Administration of dabigatran two hours before verapamil results in a negligible increase in dabigatran AUC.(1) Administration of sofosbuvir-velpatasvir-voxilaprevir (400/100/200 mg daily) increased the Cmax and AUC of a single dose of dabigatran (75 mg) by 2.87-fold and 2.61-fold, respectively.(5) Simultaneous administration of glecaprevir-pibrentasvir (300/120 mg daily) with a single dose of dabigatran (150 mg) increased the Cmax and AUC by 2.05-fold and 2.38-fold, respectively.(6) A retrospective comparative effectiveness cohort study including data from 9,886 individuals evaluated adverse bleeding rates with standard doses of oral anticoagulants with concurrent verapamil or diltiazem in patients with nonvalvular atrial fibrillation and normal kidney function. The study compared rates of bleeding following co-administration of either dabigatran, rivaroxaban, or apixaban with verapamil or diltiazem, compared to co-administration with amlodipine or metoprolol. Results of the study found that concomitant dabigatran use with verapamil or diltiazem was associated with increased overall bleeding (hazard ratio (HR) 1.52; 95% confidence interval (CI), 1.05-2.20, p<0.05) and increased overall GI bleeding (HR 2.16; 95% CI, 1.30-3.60, p<0.05) when compared to amlodipine. When compared to metoprolol, concomitant dabigatran use with verapamil or diltiazem was also associated with increased overall bleeding (HR, 1.43; 95% CI, 1.02-2.00, p<0.05) and increased overall GI bleeding (HR, 2.32; 95% CI, 1.42-3.79, p<0.05). No association was found between increased bleeding of any kind and concurrent use of rivaroxaban or apixaban with verapamil or diltiazem.(7) A summary of pharmacokinetic interactions with dabigatran and amiodarone or verapamil concluded that concurrent use is considered safe if CrCl is greater than 50 ml/min but should be avoided if CrCl is less than 50 ml/min in VTE and less than 30 ml/min for NVAF. Concurrent use with diltiazem was considered safe.(9) P-gp inhibitors include amiodarone, asunaprevir, aumolertinib, belumosudil, capmatinib, carvedilol, cimetidine, conivaptan, cyclosporine, daclatasvir, danicopan, daraxonrasib, daridorexant, diosmin, erythromycin, flibanserin, fostamatinib, ginseng, glecaprevir, imlunestrant, indinavir, itraconazole, ivacaftor, josamycin, lapatinib, ledipasvir, lonafarnib, mavorixafor, neratinib, osimertinib, pibrentasvir, posaconazole, propafenone, quinidine, ranolazine, ritonavir, selpercatinib, sotorasib, telaprevir, telithromycin, tepotinib, tezacaftor, tucatinib, valbenazine, velpatasvir, vemurafenib, vepdegestrant, verapamil, vimseltinib, voclosporin, and voxilaprevir.(1-9)

Selected P-Glycoprotein (P-GP) Inhibitors/Talazoparib

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

MECHANISM OF ACTION: Amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil (inhibitors of P-glycoprotein) may increase the absorption of talazoparib.(1)

CLINICAL EFFECTS: The concurrent administration of talazoparib with certain inhibitors of P-glycoprotein may result in elevated levels of talazoparib and signs of toxicity.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The management of this drug interaction is indication-specific. For the treatment of breast cancer, coadministration of talazoparib with the P-gp inhibitors amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil should be avoided. If coadministration cannot be avoided, the dose of talazoparib should be reduced to 0.75 mg once daily when coadministered.(1) When the P-gp inhibitor is discontinued, increase the talazoparib dose (after 3-5 half-lives of the P-gp inhibitor) to the dose used prior to initiation of the P-gp inhibitor.(1) For the treatment of metastatic castration-resistant prostate cancer, monitor patients for increased adverse reactions and adjust talazoparib dose as recommended in the prescribing information for adverse reactions.(1)

DISCUSSION: In patients with advanced solid tumors, coadministration of a single 0.5 mg dose of talazoparib with itraconazole increased talazoparib AUC and Cmax by 56% and 40%, respectively.(1) In clinical studies, coadministration of talazoparib with amiodarone, carvedilol, clarithromycin, itraconazole, or verapamil resulted in an approximately 45% increase in talazoparib exposure and an increase in the rate of talazoparib dose reduction.(1) P-gp inhibitors linked to this monograph include amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil.

Selected P-Glycoprotein (P-GP) Inhibitors/Venetoclax

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

MECHANISM OF ACTION: Venetoclax is a substrate for the P-glycoprotein (P-gp) system. P-gp inhibitors may lead to increased levels of venetoclax.(1)

CLINICAL EFFECTS: Concurrent use of P-gp inhibitors may result in elevated levels of venetoclax, increasing the risk for tumor lysis syndrome and other toxicities.(1)

PREDISPOSING FACTORS: Risk factors for tumor lysis syndrome include (1): - the ramp-up phase of venetoclax therapy when tumor burden is highest - initial magnitude of tumor burden - renal impairment The risk of venetoclax toxicities may be increased in patients with severe hepatic impairment.(1)

PATIENT MANAGEMENT: Avoid P-gp inhibitors and consider alternative treatments when possible. If a P-gp inhibitor must be used, reduce venetoclax dose by at least 50%. Monitor more closely for signs of toxicity such as tumor lysis syndrome, hematologic and non-hematologic toxicities.(1) If the P-gp inhibitor is discontinued, the manufacturer of venetoclax recommends resuming the prior (i.e. pre-inhibitor) dose of venetoclax 2 to 3 days after discontinuation of the P-gp inhibitor.(1) For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(2)

DISCUSSION: In 11 healthy subjects, a single dose of rifampin (a P-gp inhibitor) increased venetoclax maximum concentration (Cmax) and area-under-curve (AUC) by 106% and 78%, respectively.(1) In 11 previously treated NHL subjects, ketoconazole (a strong CYP3A4 inhibitor which also inhibits P-gp and BCRP) 400 mg daily for 7 days increased the Cmax and AUC of venetoclax 2.3-fold and 6.4-fold respectively.(1) In 12 healthy subjects, coadministration of azithromycin (500 mg Day 1, 250 mg for Days 2-5) decreased venetoclax Cmax and AUC by 25% and 35%. No dosage adjustment is needed when venetoclax is coadministered with azithromycin.(1) P-gp inhibitors include: amiodarone, asunaprevir, aumolertinib, belumosudil, capmatinib, carvedilol, cyclosporine, danicopan, daraxonrasib, daridorexant, diosmin, flibanserin, fostamatinib, ginseng, imlunestrant, ivacaftor, neratinib, osimertinib, pirtobrutinib, propafenone, quinidine, ranolazine, selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, tezacaftor, tepotinib, valbenazine, vemurafenib, vepdegestrant, vimseltinib, and voclosporin.(3)

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

Beta-Blockers, Oral/Rifamycins

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

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

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

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

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

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

Beta-Blockers/Anticholinesterases

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Beta-Blockers/Clonidine

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Beta-Blockers/Donepezil; Galantamine

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Beta-Blockers/Moxonidine

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

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

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Beta-Blockers; Diltiazem; Verapamil/Lacosamide

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Bisoprolol; Carvedilol; Nebivolol/Patiromer

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

MECHANISM OF ACTION: Patiromer may bind to bisoprolol, carvedilol, and nebivolol.(1)

CLINICAL EFFECTS: Concurrent use may result in decreased gastrointestinal absorption and loss of efficacy of bisoprolol, carvedilol, and nebivolol.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of patiromer recommends administering patiromer at least 3 hours before or 3 hours after bisoprolol, carvedilol, or nebivolol.(1)

DISCUSSION: An in vitro binding study found potentially clinically significant binding of bisoprolol, carvedilol, and nebivolol by patiromer. It is recommended to take these drugs 3 hours apart.(1)

Cardioselective Beta-Blockers/Epinephrine

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

MECHANISM OF ACTION: Concurrent use of beta-blockers also block the beta effects of epinephrine, which results in predomination of alpha effects. The plasma clearance of epinephrine is decreased.

CLINICAL EFFECTS: Concurrent use of epinephrine with beta-blockers may result in hypertension with reflex bradycardia. Epinephrine resistance in patients with anaphylaxis has been reported.

PREDISPOSING FACTORS: None determined.

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

DISCUSSION: A 29-year-old male undergoing elective nasal septoplasty developed severe hypertension with a blood pressure of 207/123 mmHg after topical epinephrine (1:1000) was applied to the nasal mucosa. Intravenous metoprolol was administered but the patient went into cardiogenic shock thought to be a result of unopposed alpha stimulation by the combination of epinephrine and metoprolol.(1) A study observed the differences in cardiovascular responses to subcutaneous epinephrine (given to provide hemostasis during scalp incision for craniotomy) between patients who received propranolol vs. metoprolol vs. no pretreatment. While metoprolol prevented the cardiovascular effects of epinephrine infiltration, propranolol pretreatment was associated with a highly significant increase (P less than 0.01) in mean arterial pressure and a significant decrease (P less than 0.05) in heart rate.(2) A double-blind cross-over trial studied the effects of epinephrine infusion during treatment with propranolol vs. metoprolol in 8 hypertensive patients. Patients on propranolol experienced significant increases in blood pressure and systemic vascular resistance (SVR), whereas patients on metoprolol had less increase in systolic blood pressure while the diastolic pressure remained unchanged and SVR decreased.(3) In spontaneously hypertensive rats, epinephrine in combination with pindolol induced remarkable hemodynamic changes (in particular, increase in diastolic blood pressure), which were prevented by phentolamine pretreatment, whereas epinephrine with acebutolol pretreatment induced no significant hemodynamic changes.(4)

Carvedilol; Labetalol/Insulin

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

P-Glycoprotein (P-GP) Inhibitors/Afatinib

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

MECHANISM OF ACTION: Inhibitors of P-glycoprotein (P-gp) may increase the absorption of afatinib.(1)

CLINICAL EFFECTS: The concurrent administration of afatinib with an inhibitor of P-glycoprotein may result in elevated levels of afatinib and signs of toxicity. These signs may include but are not limited to worsening diarrhea, stomatitis, skin rash/exfoliation/bullae or paronychia.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of afatinib states the afatinib dose should be reduced by 10 mg if the addition of a P-glycoprotein inhibitor is not tolerated.(1) If afatinib dose was reduced due to addition of a P-gp inhibitor, resume the previous dose after the P-gp inhibitor is discontinued.(1) The manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to afatinib.(2) The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(4)

DISCUSSION: A drug interaction study evaluated the effects of ritonavir 200 mg twice daily on afatinib exposure. Administration of ritonavir 1 hour before afatinib administration increased systemic exposure by 48%. Afatinib exposure was not changed when ritonavir was administered simultaneously with or 6 hours after afatinib dose.(1) P-glycoprotein inhibitors linked to this monograph are: amiodarone, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, clarithromycin, cobicistat, cyclosporine, danicopan, daraxonrasib, daridorexant, deutivacaftor, diosmin, dronedarone, erythromycin, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, hydroquinidine, imlunestrant, isavuconazonium, itraconazole, ivacaftor, josamycin, ketoconazole, lapatinib, ledipasvir, lonafarnib, mavorixafor, neratinib, osimertinib, posaconazole, propafenone, quinidine, ranolazine, ritonavir, saquinavir, selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, sotorasib, telaprevir, tepotinib, tucatinib, valbenazine, vemurafenib, vepdegestrant, verapamil, vimseltinib and voclosporin.(1-3)

P-Glycoprotein (P-GP) Inhibitors/Mavorixafor

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

MECHANISM OF ACTION: Mavorixafor is a substrate of the P-glycoprotein (P-gp) transporter. P-gp inhibitors may significantly increase the absorption of mavorixafor.(1)

CLINICAL EFFECTS: Concurrent administration of mavorixafor with an inhibitor of P-glycoprotein may result in elevated levels of and effects from mavorixafor, including potentially life-threatening cardiac arrhythmias, torsades de pointes, and sudden death.(1)

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.(2) 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, and/or renal/hepatic dysfunction).(2)

PATIENT MANAGEMENT: When used concomitantly with P-gp inhibitors, monitor more frequently for mavorixafor adverse effects and reduce the dose in 100 mg increments, if necessary, but not to a dose less than 200 mg.(1) The manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to mavorixafor.(4) When concurrent therapy is warranted, consider obtaining serum calcium, magnesium, and potassium levels and monitoring EKG at baseline and regular intervals. Correct any electrolyte abnormalities. Instruct patients to report any irregular heartbeat, dizziness, or fainting.

DISCUSSION: In a study with healthy subjects, itraconazole 200 mg daily (a strong CYP3A4 and P-gp inhibitor) increased the exposure to single-dose mavorixafor 200 mg similar to that from single-dose mavorixafor 400 mg alone. This suggests that itraconazole increased mavorixafor exposure by about 2-fold.(1) A study in healthy volunteers found that ritonavir 100 mg twice daily (a strong CYP3A4 inhibitor and P-gp inhibitor) increased the area-under-curve (AUC) and maximum concentration (Cmax) of single-dose mavorixafor 200 mg by 60% and 39%, respectively.(1) P-glycoprotein inhibitors linked to this monograph include: abrocitinib, Asian ginseng, asunaprevir, capmatinib, carvedilol, cyclosporine, danicopan, daridorexant, deutivacaftor, diosmin, elagolix, flibanserin, fostamatinib, ginkgo biloba, glecaprevir/pibrentasvir, ivacaftor, milk thistle, neratinib, pirtobrutinib, quercetin, rolapitant, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, velpatasvir, vilazodone, vimseltinib, and voclosporin.(1,4-6)

P-Gp Inhibitors/Daraxonrasib (<= 150 MG)

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

MECHANISM OF ACTION: Daraxonrasib is a substrate of P-gp. P-gp inhibitors may inhibit the metabolism of daraxonrasib.(1)

CLINICAL EFFECTS: Concurrent use of P-gp inhibitors may increase the levels and toxicities of daraxonrasib, including dermatologic toxicity, stomatitis, GI perforation, and interstitial lung disease/pneumonitis.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: For patients taking agents that are P-gp inhibitors, reduce the dose of daraxonrasib from 300 mg to 150 mg daily. After the P-gp inhibitor has been discontinued, resume the daraxonrasib dosage taken prior to initiating the inhibitor.(1)

DISCUSSION: In a pharmacokinetic model, quinidine 300 mg three times daily (a P-gp inhibitor) increased the area under curve (AUC) of daraxonrasib by 1.8-fold.(1) P-gp inhibitors include: abrocitinib, amiodarone, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, curcumin, danicopan, daridorexant, diosmin, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, imlunestrant, ivacaftor, lapatinib, neratinib, osimertinib, pirtobrutinib, propafenone, ranolazine, selpercatinib, tepotinib, tezacaftor, turmeric, valbenazine, velpatasvir, vemurafenib, vepdegestrant, vimseltinib, and voclosporin.(2-3)

P-Gp Inhibitors/Rimegepant

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

MECHANISM OF ACTION: Rimegepant is a calcitonin gene-related peptide receptor antagonist. Rimegepant is a substrate of the P-glycoprotein (P-gp) transporter. P-gp inhibitors may significantly increase the absorption of rimegepant.(1)

CLINICAL EFFECTS: The concurrent administration of rimegepant with an inhibitor of P-glycoprotein may result in elevated levels of rimegepant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of rimegepant recommends avoiding a second dose of rimegepant within 48 hours of a first dose when used concomitantly with P-gp inhibitors.(1) For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(2)

DISCUSSION: Rimegepant is a substrate of P-gp. Use of P-gp inhibitors may increase the exposure of rimegepant. In a study, cyclosporine (a potent P-gp and BCRP inhibitor) increased rimegepant area-under curve (AUC) and maximum concentration (Cmax) by 1.6- and 1.4-fold, respectively. Quinidine (a potent P-gp inhibitor) similarly increased rimegepant AUC and Cmax by 1.6- and 1.7-fold, respectively. Therefore, the effect of these drug interactions were concluded to be due entirely to P-gp and not BCRP.(1) P-glycoprotein inhibitors linked to this monograph include: amiodarone, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cyclosporine, danicopan, daraxonrasib, daridorexant, diosmin, flibanserin, fostamatinib, glecaprevir/pibrentasvir, imlunestrant, lapatinib, mavorixafor, osimertinib, pirtobrutinib, propafenone, quinidine, ranolazine, selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, vemurafenib, vepdegestrant, vimseltinib, and verapamil.(1-4)

P-Gp Or Bcrp Inhibitors/Ubrogepant (<= 50 MG)

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

MECHANISM OF ACTION: Inhibitors of P-glycoprotein (P-gp) or BCRP may increase the absorption of ubrogepant.(1)

CLINICAL EFFECTS: The concurrent administration of ubrogepant with an inhibitor of P-glycoprotein or BCRP may result in elevated levels of ubrogepant.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer recommends a dosage adjustment of ubrogepant when coadministered with P-gp or BCRP inhibitors. The dose of ubrogepant should not exceed 50 mg for initial dose. If a second dose of ubrogepant is needed, the dose should not exceed 50 mg.(1) For patients on concurrent therapy with vimseltinib and ubrogepant: The manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to ubrogepant.(3) For patients on daraxonrasib, the manufacturer of daraxonrasib states that it should be taken at least 4 hours apart from P-gp substrates.(4)

DISCUSSION: Ubrogepant is a substrate of P-gp and BCRP transporters. Use of P-gp or BCRP inhibitors may increase the exposure of ubrogepant. Clinical drug interaction studies with inhibitors of these transporters were not conducted. The US manufacturer of ubrogepant recommends dose adjustment if ubrogepant is coadministered with P-gp or BCRP inhibitors.(1) BCRP inhibitors linked to this monograph include: belumosudil, clopidogrel, curcumin, eltrombopag, febuxostat, fostemsavir, leniolisib, momelotinib, oteseconazole, regorafenib, resmetirom, ritonavir, rolapitant, roxadustat, tafamidis, oral tedizolid, turmeric, vadadustat, and zongertinib.(2,3,5,6) P-glycoprotein inhibitors linked to this monograph include: asunaprevir, belumosudil, capmatinib, carvedilol, danicopan, daraxonrasib, daridorexant, imlunestrant, neratinib, osimertinib, propafenone, quinidine, selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, tepotinib, valbenazine, vimseltinib, and voclosporin.(2,3,5,6)

Select P-Gp Inhibitors/Edoxaban (<= 30 MG)

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

MECHANISM OF ACTION: Edoxaban is a substrate for P-glycoprotein (P-gp). Inhibitors of P-gp may increase intestinal absorption and decrease renal tubular elimination of edoxaban.(1,2)

CLINICAL EFFECTS: Concurrent use with selected P-gp inhibitors may result in higher systemic concentrations of edoxaban which may increase the risk for bleeding.(1,2)

PREDISPOSING FACTORS: Bleeding risk may be increased in patients with creatinine clearance below 50 mL per minute(1-4). Use of multiple agents which increase edoxaban exposure or affect hemostasis would be expected to increase the risk for bleeding. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Management recommendations between approving regulatory agencies (FDA or European Medicines Agency, EMA) are conflicting. EMA approved prescribing information specifically states that dosage adjustments are not required solely for concomitant use with amiodarone, quinidine, or verapamil regardless of indication.(3,4) Potential interactions with azithromycin, clarithromycin, or oral itraconazole are not described.(3) FDA approved prescribing recommendations for edoxaban are indication specific:(2) - For prevention of stroke or embolic events due to nonvalvular atrial fibrillation, no edoxaban dose adjustments are recommended during concomitant therapy with P-glycoprotein inhibitors. - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE), the edoxaban dose should be reduced to 30 mg daily during concomitant use with azithromycin, clarithromycin, oral itraconazole, quinidine or verapamil. The manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to edoxaban.(6) Monitor patients receiving anticoagulant therapy for signs of blood loss, including decreased hemoglobin and/or 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. anti Factor Xa inhibition) 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. Discontinue edoxaban in patients with active bleeding. The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(9)

DISCUSSION: Edoxaban in vivo interaction studies have been performed for quinidine and verapamil. In vivo interaction studies have not been conducted for the remaining P-gp inhibitors linked to this monograph.(1,4) In an interaction study, the effect of repeat administration of quinidine (300 mg TID) on a single oral dose of edoxaban 60 mg was evaluated in healthy subjects. Both peak (Cmax) and total systemic exposure (AUC) to edoxaban and to the active M4 metabolite increased approximately 1.75-fold.(1) In an interaction study, the effect of repeat administration of verapamil (240 mg Verapamil SR Tablets (Calan SR) QD for 11 Days) on a single oral dose of edoxaban 60 mg on the morning of Day 10 was evaluated in healthy subjects. Total and peak systemic exposure to edoxaban increased 1.53-fold and 1.53-fold, respectively. Total and peak systemic exposure to the active M4 metabolite increased 1.31-fold and 1.28-fold, respectively.(1) Based upon the above results, patients in the DVT/PE trial had a 50% dose reduction (from 60 mg to 30 mg) during concomitant therapy with P-glycoprotein inhibitors. Approximately 0.5% of these patients required a dose reduction solely due to P-gp inhibitor use. This low rate of concurrent therapy was too small to allow for detailed statistical evaluation. Almost all of these patients were receiving quinidine or verapamil. In these patients, both trough edoxaban concentrations (Ctrough) used to evaluate bleeding risk, and total edoxaban exposure (AUC or area-under-curve) used to evaluate treatment efficacy, were lower than patients who did not require any edoxaban dose adjustment. In this DVT/PE comparator trial, subgroup analysis revealed that warfarin had numerically better efficacy than edoxaban in patients receiving P-gp inhibitors. Based upon the overall lower exposure to edoxaban in P-gp dose adjusted subjects, both EMA and FDA Office of Clinical Pharmacology (OCP) concluded that the edoxaban 50% dose reduction overcorrected for the difference in exposure.(1,4) Consequently, EMA recommended no edoxaban dose adjustments for patients receiving concomitant therapy with quinidine or verapamil.(3,4) A summary of pharmacokinetic interactions with edoxaban and verapamil concluded that if concurrent use is considered safe.(7) P-gp inhibitors linked to this interaction are: amiodarone, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan, daclatasvir, danicopan, daraxonrasib, daridorexant, diltiazem, diosmin, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, hydroquinidine, imlunestrant, indinavir, oral itraconazole, ivacaftor, josamycin, ledipasvir, lonafarnib, mavorixafor, neratinib, osimertinib, pirtobrutinib, posaconazole, propafenone, quinidine, ranolazine, selpercatinib, sotorasib, telaprevir, telithromycin, tezacaftor, tepotinib, tucatinib, valbenazine, velpatasvir, vemurafenib, vepdegestrant, verapamil, vimseltinib, and voclosporin.(8)

Select P-Gp Inhibitors/Edoxaban (> 30 MG)

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

MECHANISM OF ACTION: Edoxaban is a substrate for P-glycoprotein (P-gp). Inhibitors of P-gp may increase intestinal absorption and decrease renal tubular elimination of edoxaban.(1,2)

CLINICAL EFFECTS: Concurrent use with selected P-gp inhibitors may result in higher systemic concentrations of edoxaban which may increase the risk for bleeding.(1,2)

PREDISPOSING FACTORS: Bleeding risk may be increased in patients with creatinine clearance below 50 mL per minute(1-4). Use of multiple agents which increase edoxaban exposure or affect hemostasis would be expected to increase the risk for bleeding. The risk for bleeding episodes may be greater in patients with disease-associated factors (e.g. thrombocytopenia). Drug associated risk factors include concurrent use of multiple drugs which inhibit anticoagulant/antiplatelet metabolism and/or have an inherent risk for bleeding (e.g. NSAIDs).

PATIENT MANAGEMENT: Management recommendations between approving regulatory agencies (FDA or European Medicines Agency, EMA) are conflicting. EMA approved prescribing information specifically states that dosage adjustments are not required solely for concomitant use with amiodarone, quinidine, or verapamil regardless of indication.(3,4) Potential interactions with azithromycin, clarithromycin, or oral itraconazole are not described.(3) FDA approved prescribing recommendations for edoxaban are indication specific:(2) - For prevention of stroke or embolic events due to nonvalvular atrial fibrillation, no edoxaban dose adjustments are recommended during concomitant therapy with P-glycoprotein inhibitors. - For treatment of deep vein thrombosis (DVT) or pulmonary embolism (PE), the edoxaban dose should be reduced to 30 mg daily during concomitant use with azithromycin, clarithromycin, oral itraconazole, quinidine or verapamil. The manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to edoxaban.(6) Monitor patients receiving anticoagulant therapy for signs of blood loss, including decreased hemoglobin and/or 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. anti Factor Xa inhibition) 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. Discontinue edoxaban in patients with active bleeding. The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(9)

DISCUSSION: Edoxaban in vivo interaction studies have been performed for quinidine and verapamil. In vivo interaction studies have not been conducted for the remaining P-gp inhibitors linked to this monograph.(1,4) In an interaction study, the effect of repeat administration of quinidine (300 mg TID) on a single oral dose of edoxaban 60 mg was evaluated in healthy subjects. Both peak (Cmax) and total systemic exposure (AUC) to edoxaban and to the active M4 metabolite increased approximately 1.75-fold.(1) In an interaction study, the effect of repeat administration of verapamil (240 mg Verapamil SR Tablets (Calan SR) QD for 11 Days) on a single oral dose of edoxaban 60 mg on the morning of Day 10 was evaluated in healthy subjects. Total and peak systemic exposure to edoxaban increased 1.53-fold and 1.53-fold, respectively. Total and peak systemic exposure to the active M4 metabolite increased 1.31-fold and 1.28-fold, respectively.(1) Based upon the above results, patients in the DVT/PE trial had a 50% dose reduction (from 60 mg to 30 mg) during concomitant therapy with P-glycoprotein inhibitors. Approximately 0.5% of these patients required a dose reduction solely due to P-gp inhibitor use. This low rate of concurrent therapy was too small to allow for detailed statistical evaluation. Almost all of these patients were receiving quinidine or verapamil. In these patients, both trough edoxaban concentrations (Ctrough) used to evaluate bleeding risk, and total edoxaban exposure (AUC or area-under-curve) used to evaluate treatment efficacy, were lower than patients who did not require any edoxaban dose adjustment. In this DVT/PE comparator trial, subgroup analysis revealed that warfarin had numerically better efficacy than edoxaban in patients receiving P-gp inhibitors. Based upon the overall lower exposure to edoxaban in P-gp dose adjusted subjects, both EMA and FDA Office of Clinical Pharmacology (OCP) concluded that the edoxaban 50% dose reduction overcorrected for the difference in exposure.(1,4) Consequently, EMA recommended no edoxaban dose adjustments for patients receiving concomitant therapy with quinidine or verapamil.(3,4) A summary of pharmacokinetic interactions with edoxaban and verapamil concluded that if concurrent use is considered safe.(7) P-gp inhibitors linked to this interaction are: amiodarone, asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan, daclatasvir, danicopan, daraxonrasib, daridorexant, diltiazem, diosmin, flibanserin, fostamatinib, ginseng, glecaprevir/pibrentasvir, hydroquinidine, imlunestrant, indinavir, oral itraconazole, ivacaftor, josamycin, ledipasvir, lonafarnib, neratinib, osimertinib, pirtobrutinib, posaconazole, propafenone, quinidine, ranolazine, selpercatinib, sotorasib, telaprevir, telithromycin, tezacaftor, tepotinib, tucatinib, valbenazine, velpatasvir, vemurafenib, vepdegestrant, verapamil, vimseltinib, and voclosporin.(8)

Selected Antihypertensive Agents/Selected Maois

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

MECHANISM OF ACTION: Both MAOIs and antihypertensive agents may increase the risk of postural hypotension.(1,2)

CLINICAL EFFECTS: Postural hypotension may occur with concurrent therapy of MAOIs and antihypertensive agents.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturer of phenelzine states all patients should be followed closely for symptoms of postural hypotension. Hypotensive side effects have occurred in patients who have been hypertensive and normotensive, as well as hypotensive at initiation of phenelzine.(1) The manufacturer of tranylcypromine states hypotension has been observed most commonly but not exclusively in patients with pre-existing hypertension. Tranylcypromine doses greater than 30 mg daily have a major side effect of postural hypotension and can lead to syncope. Gradual dose titration is recommended to decrease risk of postural hypotension. Combined use with other agents known to cause hypotension have shown to have additive side effects and should be monitored closely.(2) Monitor the patient for signs and symptoms of postural hypotension including dizziness, lightheadedness, or weakness, especially upon standing. Monitor blood pressure as well as orthostatic vitals and adjust antihypertensive therapy, including decreasing the dose, dividing doses, or scheduling doses at bedtime, as needed to maintain goal blood pressure. If blood pressure remains hypotensive, consider decreasing the dose of phenelzine or tranylcypromine. In some cases, discontinuation of one or both agents may be necessary.(3) Normotensive patients on stable antihypertensive therapy who are started on either phenelzine or tranylcypromine may be at increased risk for hypotension. Hypertensive patients on stable phenelzine or tranylcypromine who require antihypertensive therapy would be at decreased risk for hypotension.

DISCUSSION: A review article describes the pharmacology of phenelzine and tranylcypromine as non-selective MAOIs which inhibit both type A and type B substrates. Orthostatic hypotension is described as the most common MAOI side effect and usually occurs between initiation and the first 3-4 weeks of therapy.(3) In a double-blind study, 71 patients were randomized to receive a 4-week trial of either tranylcypromine, amitriptyline, or the combination. The number of patients reporting dizziness at 4 weeks was not different between the three treatment groups (tranylcypromine 52.4%; amitriptyline 65%; combination 66.7%). Blood pressure (BP) assessment noted a significant drop in standing BP in the tranylcypromine group compared to baseline (systolic BP change = -10 mmHg; p<0.02 and diastolic BP change = -9 mmHg; p<0.02). Combination therapy also had a significant drop in standing BP compared to baseline (systolic BP change = -9 mmHg; p<0.02). Patients receiving amitriptyline had no significant change in BP from baseline at 4 weeks. All three groups had a trend toward increasing orthostatic hypotension in BP changes from lying to standing. The change in orthostatic hypotension was significant in the amitriptyline group with an average systolic BP orthostatic drop of -9 mmHg (p<0.05).(4) A randomized, double-blind study of 16 inpatients with major depressive disorder were treated with either phenelzine or tranylcypromine. Cardiovascular assessments were completed at baseline and after 6 weeks of treatment. After 6 weeks, 5/7 patients (71%) who received phenelzine had a decrease in standing systolic BP greater than 20 mmHg from baseline. Head-up tilt systolic and diastolic BP decreased from baseline in patients on phenelzine (98/61 mmHg v. 127/65 mmHg, respectively; systolic change p=0.02 and diastolic change p=0.02). After 6 weeks, 6/9 patients (67%) who received tranylcypromine had a decrease in standing systolic BP greater than 20 mmHg from baseline. Head-up tilt systolic and diastolic BP decreased from baseline in patients on tranylcypromine (113/71 mmHg v. 133/69 mmHg, respectively; systolic change p=0.09 and diastolic change p=0.07).(5) Selected MAOIs linked to this monograph include: phenelzine and tranylcypromine. Selected antihypertensive agents include: ACE inhibitors, alpha blockers, ARBs, beta blockers, calcium channel blockers, aprocitentan, clonidine, hydralazine, moxonidine, and sparsentan.

Selected Antihypertensives And Vasodilators/Apomorphine

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

MECHANISM OF ACTION: Apomorphine causes dose-dependent decreases in blood pressure. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1)

CLINICAL EFFECTS: Concurrent use of antihypertensives and apomorphine may result in orthostatic hypotension with or without dizziness, nausea, or syncope.(1)

PREDISPOSING FACTORS: The risk of orthostatic hypotension may be increased during dose escalation of apomorphine and in patients with renal or hepatic impairment.(1)

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. Counsel patients about the risk of orthostatic hypotension.(1)

DISCUSSION: Healthy volunteers who took sublingual nitroglycerin (0.4 mg) concomitantly with apomorphine experienced a mean largest decrease in supine systolic blood pressure (SBP) of 9.7 mm Hg and in supine diastolic blood pressure (DBP) of 9.3 mm Hg, and a mean largest decrease in standing SBP and DBP of 14.3 mm Hg and 13.5 mm Hg, respectively. The maximum decrease in SBP and DBP was 65 mm Hg and 43 mm Hg, respectively. When apomorphine was taken alone, the mean largest decrease in supine SBP and DBP was 6.1 mm Hg and 7.3 mm Hg, respectively, and in standing SBP and DBP was 6.7 mm Hg and 8.4 mm Hg, respectively.(1)

Selected Antihypertensives/Tizanidine

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

MECHANISM OF ACTION: Tizanidine is an alpha-2 agonist. Concurrent use with antihypertensive agents may result in additive effects on blood pressure.(1)

CLINICAL EFFECTS: Concurrent use of antihypertensives and tizanidine may result in hypotension.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving concurrent therapy should be monitored for hypotension. The risk of hypotension may be decreased by careful titration of tizanidine dosages and monitoring for hypotension prior to dose advancement. Counsel patients about the risk of orthostatic hypotension.(1)

DISCUSSION: Severe hypotension has been reported following the addition of tizanidine to existing lisinopril therapy.(2-4)

Selected Beta-Blockers/Amiodarone; Dronedarone

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Selected Beta-Blockers/Selected Calcium Channel Blockers

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

MECHANISM OF ACTION: Synergistic pharmacologic activity.

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

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

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

DISCUSSION: Coadministration of these classes of drugs may be effective in the treatment of angina pectoris and hypertension. Patients should be screened in order to determine who should receive this combination of agents. The concurrent use of mibefradil and beta-blockers in patients with low heart rates may unmask underlying sick sinus syndrome. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Selected Beta-Blockers/Theophyllines

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

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

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

PREDISPOSING FACTORS: Cigarette smoking may exacerbate this interaction.

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

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

Selected P-Glycoprotein (P-GP) Inhibitors/Betrixaban

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

MECHANISM OF ACTION: Betrixaban is a substrate for the P-glycoprotein (P-gp) system. Inhibition of intestinal P-gp leads to increased absorption of betrixaban.(1)

CLINICAL EFFECTS: The concurrent use betrixaban with P-gp inhibitors may lead to elevated plasma levels of betrixaban, increasing the risk for bleeding.

PREDISPOSING FACTORS: Factors associated with an increased risk for bleeding include renal impairment, concomitant use of P-gp inhibitors, coexisting conditions (e.g. recent trauma) or use of drugs (e.g. NSAIDs) associated with bleeding risk, and patient weight < 50 kg.(1)

PATIENT MANAGEMENT: Assess renal function and evaluate patient for other pre-existing risk factors for bleeding prior to initiating concurrent therapy. The concurrent use of betrixaban and P-gp inhibitors should be avoided in patients with severe renal impairment (CrCl less than 30 ml/min).(1) The recommended dose for patients receiving or starting concomitant P-gp inhibitors is an initial single dose of 80 mg followed by 40 mg once daily. The recommended duration of treatment is 35 to 42 days.(1) Note that if betrixaban is used with the combination of darunavir and cobicistat, dose adjustment of betrixaban is not necessary.(2) The manufacturer of vimseltinib states concurrent use with P-gp substrates should be avoided. If concurrent use cannot be avoided, take vimseltinib at least 4 hours prior to betrixaban.(3) Careful monitoring for signs and symptoms of bleeding is warranted during concurrent therapy. Consider regular monitoring of hemoglobin, platelet levels, and/or activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT). Instruct patients to report any signs and symptoms of bleeding, such as bleeding from the eyes, gums or nose; unusual bruising; dark stools; red or dark brown urine; and/or abdominal pain or swelling.(1) The anticoagulant effect of betrixaban is expected to persist for at least 72 hours after the last dose. The manufacturer of daraxonrasib states P-gp substrates should be administered at least 4 hours apart from daraxonrasib.(8)

DISCUSSION: In the APEX randomized, double-blind study the incidence of major or clinically relevant non-major bleeds (CRNM) in the betrixaban 40mg and 80 mg group was higher in patients taking concomitant P-gp inhibitors (2.8% vs. 4.1% vs. 4.7%).(4) In a study in 12 subjects, concomitant administration of a single dose of betrixaban (40 mg) following a 5-day regimen of ketoconazole (200 mg twice daily) resulted in an increase in betrixaban's maximum concentration (Cmax) and area-under-the-curve (AUC) of 2.3-fold and 2.3-fold, respectively.(5) An open-label study looking at concomitant administration of a single dose of betrixaban with verapamil in 18 subjects found an increase in betrixaban's Cmax and AUC of approximately 4.7-fold and 3-fold, respectively.(5) In a study, concomitant administration of betrixaban (80 mg) with amiodarone resulted in an increase in betrixaban's Cmax by 143%.(5) A summary of pharmacokinetic interactions with betrixaban and amiodarone, diltiazem, or verapamil concluded that if concurrent use is warranted, the betrixaban dose should be reduced to 80 mg once then 40 mg daily. Use should be avoided if CrCl is less than 30 ml/min.(6) P-gp inhibitors include asunaprevir, aumolertinib, azithromycin, belumosudil, capmatinib, carvedilol, cimetidine, clarithromycin, cobicistat, conivaptan, cyclosporine, daclatasvir, danicopan, daraxonrasib, daridorexant, diltiazem, diosmin, dronedarone, erythromycin, flibanserin, fostamatinib, ginseng, glecaprevir, hydroquinidine, imlunestrant, indinavir, itraconazole, ivacaftor, josamycin, lapatinib, ledipasvir, lonafarnib, lopinavir, mavorixafor, neratinib, osimertinib, pibrentasvir, pirtobrutinib, posaconazole, propafenone, quinidine, ranolazine, ritonavir, selpercatinib, sofosbuvir/velpatasvir/voxilaprevir, sotorasib, telaprevir, telithromycin, tepotinib, tezacaftor, tucatinib, valbenazine, velpatasvir, vemurafenib, vepdegestrant, vimseltinib, voclosporin and voxilaprevir.(1,4-7)

Slt Non-Cardioselective B-Blockers/Nateglinide; Repaglinide

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Systemic Non-Cardioselective Beta-Blockers/Sulfonylureas

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

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

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

PREDISPOSING FACTORS: None determined.

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

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

Bronchial asthma or related bronchospastic conditions.

Second or third degree AV block.

Sick sinus syndrome or severe bradycardia (unless permanent pacemaker is in place).

Cardiogenic shock or decompensated heart failure requiring IV inotropic therapy; initiate carvedilol only after the patient is weaned from IV therapy.

Clinically apparent or otherwise severe hepatic impairment.

History of serious hypersensitivity reaction (e.g., Stevens-Johnson syndrome, anaphylactic reaction, angioedema) to carvedilol or any ingredient in the formulation.

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

• Acute decompensated heart failure
• Chronic obstructive pulmonary disease
• Hypotension
• Pregnancy
• Sick sinus syndrome
• Sinus bradycardia

• CYp2d6 poor metabolizer
• Diabetes mellitus
• First degree atrioventricular heart block
• Hypoglycemic disorder
• Intraoperative floppy iris syndrome
• Myasthenia gravis
• Peripheral vascular disease
• Prinzmetal angina
• Severe hepatic disease

Adverse effects reported in 5% or more of patients with heart failure receiving immediate-release carvedilol tablets include dizziness, headache, fatigue, asthenia, arthralgia, hypotension, bradycardia, generalized edema, diarrhea, nausea, vomiting, hyperglycemia, weight gain, increased BUN, increased nonprotein nitrogen (NPN), increased cough, and abnormal vision.

Adverse effects reported in patients with left ventricular dysfunction following MI receiving immediate-release carvedilol tablets generally were similar to those in patients receiving the drug for the treatment of heart failure. Additional adverse effects reported in 3% or more of such patients include anemia, dyspnea, and pulmonary edema.

Adverse effects reported in 2% or more of patients receiving immediate-release carvedilol tablets for the treatment of hypertension include dizziness, bradycardia, diarrhea, insomnia, and postural hypotension.

Adverse effects reported in 2% or more of patients receiving extended-release carvedilol phosphate capsules for the treatment of hypertension include nasopharyngitis, dizziness, nausea, and peripheral edema.

More Frequent

• Bradycardia
• Dyspnea
• Hyperglycemia
• Hypotension
• Orthostatic hypotension
• Peripheral edema

Less Frequent

• Anemia
• Atrioventricular block
• Depression
• Edema
• Increased alanine transaminase
• Increased aspartate transaminase
• Jaundice
• Pulmonary edema
• Purpura
• Thrombocytopenic disorder

Rare or Very Rare

• Anaphylaxis
• Angina
• Angioedema
• Aplastic anemia
• Asthma exacerbation
• Bronchospastic pulmonary disease
• Erythema multiforme
• Hypovolemia
• Interstitial pneumonitis
• Intraoperative floppy iris syndrome
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Stevens-johnson syndrome
• Syncope
• Toxic epidermal necrolysis
• Urticaria
• Worsening of chronic heart failure

More Frequent

• Back pain
• Diarrhea
• Dizziness
• Fatigue
• Paresthesia
• Weight gain

Less Frequent

• Arthralgia
• Blurred vision
• Chest pain
• Cough
• Cramps
• Drowsy
• Erectile dysfunction
• Fever
• Flu-like symptoms
• General weakness
• Headache disorder
• Hematuria
• Hypercholesterolemia
• Hyperhidrosis
• Hypoesthesia
• Insomnia
• Malaise
• Myalgia
• Nausea
• Palpitations
• Pharyngitis
• Proteinuria
• Pruritus of skin
• Rhinitis
• Vertigo
• Vomiting

Rare or Very Rare

• Black tarry stools
• Hyperuricemia
• Periodontitis
• Urinary incontinence

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Safety and efficacy not established in children younger than 18 years of age.

In a clinical trial in pediatric patients (mean age 6 years, range 2 months to 17 years) with chronic heart failure (NYHA class II-IV), carvedilol resulted in beta-blockade activity as demonstrated by a placebo-corrected heart rate reduction of 4-6 beats/minute; however, no clinically important effect on treatment outcome was observed after 8 months of follow-up. Common adverse effects included chest pain, dizziness, and dyspnea.

Category C. (See Users Guide.)

Crosses the placenta in rats. Perinatal and neonatal distress have been reported with other alpha- and beta-blockers.

Distributed into milk in rats; not known whether distributed into human milk. Because of the risk of adverse effects in the infant, discontinue nursing or the drug, taking into account the importance of the drug to the woman.

No substantial differences in safety or efficacy relative to younger adults, but possibility exists of increased sensitivity to carvedilol in some individuals. Some clinicians suggest using a reduced initial carvedilol dosage in geriatric patients, since such patients are at increased risk of developing orthostatic hypotension and experience is limited regarding the use of the drug in patients 75 years of age or older. Plasma concentrations of carvedilol are about 50% higher in geriatric individuals than in younger individuals.