Erythromycin

7 DRUG INTERACTIONS • Avanafil can potentiate the hypotensive effect of nitrates, alpha-blockers, antihypertensives, and alcohol ( 7.1 ) • CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, erythromycin) increase avanafil exposure ( 7.2 ) 7.1 Potential for Pharmacodynamic Interactions with Avanafil Nitrates Administration of avanafil to patients who are using any form of organic nitrate, is contraindicated. Moderate CYP3A4 Inhibitors Erythromycin (500 mg twice daily) increased avanafil 200 mg single-dose C max and AUC equal to approximately 2-fold and 3-fold, respectively, and prolonged the half-life of avanafil to approximately 8 hours in healthy volunteers. Moderate CYP3A4 inhibitors (e.g., erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil) would be expected to have similar effects.

CYP3A4 inhibitor that can increase systemic budesonide concentrations. Avoid use.

Antagonism demonstrated between clindamycin and erythromycin in vitro; these two drugs should not be administered concurrently due to possible clinical significance.

Should not be used in combination with topical or oral erythromycin-containing products due to possible antagonism to clindamycin's antimicrobial component.

Should not be used in combination with topical or oral erythromycin-containing products due to antagonism between erythromycin and clindamycin demonstrated in vitro.

Should not be used in combination with clindamycin phosphate and tretinoin gel due to clindamycin component. In vitro studies show antagonism between these antimicrobials.

Should not be used in combination due to possible antagonism between clindamycin and erythromycin. In-vitro studies show antagonism between these antimicrobials.

Should not be used in combination due to clindamycin component. In vitro studies show antagonism between erythromycin and clindamycin, though clinical significance is unknown.

Co-administration associated with acute ergot toxicity characterized by vasospasm and ischemia of extremities and other tissues including central nervous system.

Strong CYP3A4 inhibitor; rare reports of serious adverse events including vasospasm leading to cerebral ischemia and ischemia of extremities.

Cases of life-threatening interactions have been reported. Erythromycin inhibits cytochrome P450 3A4, resulting in elevation of disopyramide plasma levels.

Co-administration associated with acute ergot toxicity characterized by vasospasm and ischemia of extremities and other tissues including central nervous system.

] Ezetimibe and Simvastatin Tablets Drug Interactions Associated With Increased Risk of Myopathy/Rhabdomyolysis ( 2.3 , 2.4 , 4 , 5.1 , 7.1 , 7.2 , 7.3 , 7.8 , 12.3 ) Interacting Agents Prescribing Recommendations Strong CYP3A4 Inhibitors, (e.g., itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with ezetimibe and simvastatin tablets Niacin (≥1 g/day) For Chinese patients, not recommended with ezetimibe and simvastatin tablets Verapamil, diltiazem, dronedarone Do not exceed 10 mg/10 mg ezetimibe and simvastatin tablets, daily Amiodarone, amlodipine, ranolazine Do not exceed 10 mg/20 mg ezetimibe and simvastatin tablets, daily Lomitapide For patients with HoFH, do not exceed 10 mg/20 mg ezetimibe and simvastatin tablets 1 Daptomycin Temporally suspend ezetimibe and simvastatin tablets Grapefruit juice Avoid grapefruit juice 1. If treatment with itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with ezetimibe and simvastatin tablets must be suspended during the course of treatment.

Moderate CYP3A4 inhibitor; concomitant use is contraindicated due to increased risk of hypotension and syncope.

Concomitant use of moderate CYP3A4 inhibitors (such as amprenavir, aprepitant, atazanavir, ciprofloxacin, crizotinib, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fosamprenavir, imatinib, verapamil) has not been studied, but concomitant use with lomitapide is contraindicated since lomitapide exposure will likely increase significantly in the presence of these inhibitors.

Strong CYP3A4 inhibitor increases risk of myopathy by reducing lovastatin elimination.

Potent CYP 3A4 inhibitor; rare reports of serious adverse events including vasospasm leading to cerebral ischemia and extremity ischemia with ergot alkaloids.

CYP3A4 inhibitor may increase codeine plasma concentrations and morphine levels, potentially causing fatal respiratory depression. Avoid use; if necessary, monitor frequently.

CYP3A4 inhibitor; simultaneous use with both CYP2D6 and CYP3A4 inhibitors should be avoided due to increased risk of proarrhythmia.

CYP3A4 inhibitor causing increased quinine plasma levels. Concomitant administration should be avoided.

Strong CYP3A4/P-gp inhibitor that increases sirolimus concentrations. Avoid concomitant use; consider alternative agents.

7 DRUG INTERACTIONS Sildenafil citrate can potentiate the hypotensive effects of nitrates, alpha blockers, and anti-hypertensives ( 4.1 , 5.5 , 7.1 , 7.2 , 7.3 , 12.2 ) With concomitant use of alpha blockers, initiate sildenafil citrate at 25 mg dose ( 2.3 ) CYP3A4 inhibitors (e.g., ritonavir, ketoconazole, itraconazole, erythromycin): Increase sildenafil citrate exposure ( 2.4 , 7.4 , 12.3 ) Ritonavir: Do not exceed a maximum single dose of 25 mg in a 48 hour period ( 2.4 , 5.6 ) Erythromycin or strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, saquinavir): Consider a starting dose of 25 mg ( 2.4 , 7.4 ) 7.1 Nitrates Administration of sildenafil tablets with nitric oxide donors such as organic nitrates or organic nitrites in any form is contraindicated. Co-administration of erythromycin, a moderate CYP3A4 inhibitor, resulted in a 160% and 182% increases in sildenafil C max and AUC, respectively. A starting dose of 25 mg of sildenafil tablets should be considered in patients taking erythromycin or strong CYP3A4 inhibitors (such as saquinavir, ketoconazole, itraconazole) [ see Dosage and Administration ( 2.4 ), Clinical Pharmacology ( 12.3 ) ] .

7 DRUG INTERACTIONS • Sildenafil can potentiate the hypotensive effects of nitrates, alpha blockers, and anti-hypertensives ( 4.1 , 5.5 , 7.1 , 7.2 , 7.3 , 12.2 ) • With concomitant use of alpha blockers, initiate sildenafil at 25 mg dose ( 2.3 ) • CYP3A4 inhibitors (e.g., ritonavir, ketoconazole, itraconazole, erythromycin): Increase sildenafil exposure ( 2.4 , 7.4 , 12.3 ) o Ritonavir: Do not exceed a maximum single dose of 25 mg in a 48 hour period ( 2.4 , 5.6 ) o Erythromycin or strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, saquinavir): Consider a starting dose of 25 mg ( 2.4 , 7.4 ) 7.1 Nitrates Administration of sildenafil with nitric oxide donors such as organic nitrates or organic nitrites in any form is contraindicated. Co-administration of erythromycin, a moderate CYP3A4 inhibitor, resulted in a 160% and 182% increases in sildenafil C max and AUC, respectively. A starting dose of 25 mg of sildenafil should be considered in patients taking erythromycin or strong CYP3A4 inhibitors (such as saquinavir, ketoconazole, itraconazole) [ see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) ].

7 DRUG INTERACTIONS Drug Interactions Associated with increased Risk of Risk of Myopathy/Rhabdomyolysis ( 2.3 , 2.4 , 4 , 5.1 , 7.1 , 7.2 , 7.3 , 12.3 ) Interacting Agents Prescribing Recommendations Strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole,posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, boceprevir, telaprevir, nefazodone, cobicistat-containing products), gemfibrozil, cyclosporine, danazol Contraindicated with simvastatin Niacin (≥1 g/day) For Chinese patients, notrecommended with simvastatin Verapamil, diltiazem, dronedarone Do not exceed 10 mg simvastatin daily Amiodarone, amlodipine, ranolazine Do not exceed 20 mg simvastatin daily Lomitapide For patients with HoFH, do not exceed 20 mg simvastatin daily* Daptomycin Temporarily suspend simvastatin Grapefruit juice Avoid grapefruit juice *For patients with HoFH who have been taking 80 mg simvastatin chronically (e.g., for 12 months or more) without evidence of muscle toxicity, do not exceed 40 mg simvastatin when taking lomitapide. If treatment with itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin or telithromycin is unavoidable, therapy with simvastatin must be suspended during the course of treatment.

In vivo studies Do not use vardenafil orally disintegrating tablet with moderate and strong CYP3A4 inhibitors such as erythromycin, grapefruit juice, clarithromycin, ketoconazole, itraconazole, indinavir, saquinavir, atazanavir, ritonavir as the systemic concentration of vardenafil is increased in their presence [see Warnings and Precautions (5) and Dosage and Administration ( 2.4 )] . Moderate CYP3A4 inhibitors Erythromycin (500 mg t.i.d.) produced a 4-fold increase in vardenafil AUC and a 3-fold increase in vardenafil C max when co-administered with vardenafil 5 mg in healthy volunteers [see Dosage and Administration ( 2 ) and Warnings and Precautions ( 5 )].

CYP3A4 Inhibitors The concomitant use of acetaminophen and codeine phosphate tablets and CYP3A4 inhibitors, such as macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), and protease inhibitors (e.g., ritonavir), may result in an increase in codeine plasma concentrations, with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of acetaminophen and codeine phosphate tablets is achieved ( see WARNINGS ).

Erythromycin may increase the pharmacologic effects of alprazolam through decreased clearance.

Hypotension risk with concomitant erythromycin use. CYP3A4-metabolized calcium channel blocker.

No drug interaction studies have been conducted with amlodipine besylate and atorvastatin calcium and other drugs, although studies have been conducted in the individual amlodipine and atorvastatin components, as described below: Amlodipine Increased Risk of Myopathy and Rhabdomyolysis ( 2 , 5.1 , 7.3 , 12.3 ) Cyclosporine, tipranavir plus ritonavir, glecaprevir plus pibrentasvir Avoid atorvastatin Clarithromycin, itraconazole, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir,letermovir Do not exceed 20 mg atorvastatin daily Nelfinavir Do not exceed 40 mg atorvastatin daily Lopinavir plus ritonavir, simeprevir, fibric acid derivatives, erythromycin, azole antifungals, lipid-modifying doses of niacin, colchicine Consider the risk/benefit of concomitant use with atorvastatin Other Lipid-Lowering Medications: Increased risk of myopathy (7) . Examples: Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole.

Rhabdomyolysis reported with concomitant erythromycin use due to CYP3A4 inhibition increasing statin levels.

7 DRUG INTERACTIONS Drug Interactions that may Increase the Risk of Myopathy and Rhabdomyolysis with atorvastatin ( 2.6 , 5.1 , 7.1 , 12.3 ) Interacting Agents Prescribing Recommendations Cyclosporine, tipranavir plus ritonavir, glecaprevir plus pibrentasvir Avoid atorvastatin Clarithromycin, itraconazole, saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir, elbasvir plus grazoprevir, letermovir Do not exceed 20 mg atorvastatin daily Nelfinavir Do not exceed 40 mg atorvastatin daily Lopinavir plus ritonavir, simeprevir, fibric acid derivatives, erythromycin, azole antifungals, lipid-modifying doses of niacin, colchicine Consider the risk/benefit of concomitant use with atorvastatin • Other Lipid-Lowering Medications: Use with fibrate products or lipid-modifying doses (≥1 g/day) of niacin increases the risk of adverse skeletal muscle effects. Examples: Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole.

CYP3A4 inhibitor increases hydrocodone plasma concentration, resulting in increased or prolonged opioid effects including respiratory depression and sedation.

Moderate CYP3A inhibitor; when combined with a CYP2C9 inhibitor, will likely lead to large increases in bosentan plasma concentrations. Co-administration not recommended.

Macrolide antibiotic erythromycin significantly increases bromocriptine plasma levels (AUC increased 3.7-fold, Cmax increased 4.6-fold).

CYP3A4 inhibitor that increases buprenorphine plasma concentration, resulting in increased or prolonged opioid effects and respiratory depression risk.

CYP3A4 inhibitor that increases buprenorphine plasma concentration, resulting in increased or prolonged opioid effects.

CYP3A4 inhibitor that can increase plasma concentration of buprenorphine, resulting in increased or prolonged opioid effects and respiratory depression.

CYP3A4 inhibitor; 5-6 fold increase in buspirone concentrations with increased incidence of side effects; low dose buspirone recommended.

CYP3A4 inhibitor may increase codeine plasma concentrations and morphine levels, potentially causing fatal respiratory depression, particularly when added after stable dosing.

CYP3A4 inhibitor may increase codeine plasma concentrations and morphine levels, potentially causing fatal respiratory depression, particularly when added after stable dosing.

Moderate CYP3A4 inhibitor increases cilostazol exposure. Requires cilostazol dose reduction to 50 mg twice daily.

Moderate CYP3A inhibitor. If short-term use unavoidable, reduce cobimetinib dose from 60 mg to 20 mg.

CYP3A4 inhibitor may increase codeine plasma concentrations leading to greater morphine levels and potentially fatal respiratory depression. Avoid concomitant use.

CYP3A4 inhibitor that increases codeine plasma concentrations and morphine levels, potentially causing fatal respiratory depression.

Toxicities have also been reported when colchicine is administered with inhibitors of CYP3A4 that may not be potent inhibitors of P-gp (e.g., grapefruit juice, erythromycin, verapamil), or inhibitors of P-gp that may not be potent inhibitors of CYP3A4 (e.g., cyclosporine). 7.1 CYP3A4 The concomitant use of colchicine capsules and CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole, grapefruit juice, erythromycin, verapamil, etc.) should be avoided due to the potential for serious and life-threatening toxicity [see Warnings and Precautions (5.3) and Clinical Pharmacology (12) ] .

Erythromycin inhibits cytochrome P450 3A4, resulting in increased plasma concentrations of corticosteroids.

Concomitant administration with erythromycin results in elevated digoxin serum levels.

Hypotension risk with concomitant erythromycin use. CYP3A4-metabolized calcium channel blocker.

Moderate CYP3A4 inhibitor that significantly increases everolimus Cmax and AUC. Consider dose adjustment.

Moderate CYP3A4 inhibitor significantly increases everolimus Cmax, AUC, and half-life; dose adjustment should be considered.

CYP3A4 inhibitor resulting in approximately 2.5-fold increase in AUC and Cmax with about 2-fold prolongation in half-life of felodipine.

CYP3A4 inhibitor that increases fentanyl plasma concentration, resulting in increased or prolonged opioid effects, respiratory depression, and sedation.

CYP3A4 inhibitor that increases fentanyl plasma concentration, resulting in increased or prolonged opioid effects, particularly respiratory depression and sedation.

CYP3A4 inhibitor; concomitant use can increase plasma concentration of fentanyl, resulting in increased or prolonged opioid effects, respiratory depression, and sedation.

QT-prolonging drug with known torsades de pointes risk. Combined with fingolimod's QT prolongation and bradycardia effects, patients require overnight continuous ECG monitoring in medical facility.

QT-prolonging drug associated with torsades de pointes risk. Patients require overnight continuous ECG monitoring in medical facility during fingolimod initiation.

CYP3A4 inhibitor that increases hydrocodone plasma concentration, resulting in increased or prolonged opioid effects including respiratory depression and sedation.

CYP3A4 inhibitor that increases hydrocodone plasma concentration, resulting in increased or prolonged opioid effects and potential respiratory depression.

CYP3A4 inhibitor that can increase plasma concentration of hydrocodone, resulting in increased or prolonged opioid effects.

CYP3A4 inhibitor that can increase hydrocodone plasma concentration, resulting in increased or prolonged opioid effects and respiratory depression.

CYP3A4 inhibitor that increases hydrocodone plasma concentration, resulting in increased or prolonged opioid effects including respiratory depression and sedation.

CYP3A4 inhibitor that can increase plasma concentration of hydrocodone, resulting in increased or prolonged opioid effects.

Macrolide antibiotic causing significant decrease in corticosteroid clearance, potentially increasing corticosteroid levels.

Moderate CYP3A4 inhibitor increases lurasidone exposure. Lurasidone dose should be reduced to half the original level.

Concomitant use can increase meperidine plasma concentration, resulting in increased or prolonged opioid effects including respiratory depression.

CYP3A4 inhibitor that increases methadone plasma concentration, resulting in increased opioid effects and potential fatal overdose.

CYP3A4 inhibitor that increases methadone plasma concentration, resulting in increased opioid effects and risk of fatal overdose.

Macrolide antibiotics cause significant decrease in corticosteroid clearance, increasing corticosteroid levels.

May result in prolonged sedation due to decreased plasma clearance. Approximately doubled the half-life of midazolam.

Inhibits P450-3A4 enzyme system, reducing midazolam clearance and approximately doubling its half-life, resulting in prolonged sedation.

7 DRUG INTERACTIONS Moderate CYP3A4 inhibitors (e.g., diltiazem, erythromycin, verapamil) : Increased naloxegol concentrations; avoid concomitant use; if unavoidable, reduce dosage to 12.5 mg once daily and monitor for adverse reactions. Moderate CYP3A4 inhibitors (e.g., diltiazem, erythromycin, verapamil) Avoid use with moderate CYP3A4 inhibitors; if unavoidable, decrease the dosage of MOVANTIK to 12.5 mg once daily and monitor for adverse reactions [see Dosage and Administration (2.4) ] .

CYP3A inhibitor that may increase nifedipine exposure. Careful monitoring and dose adjustment necessary; consider lowest dose.

Increased anticoagulant effects when used concomitantly with erythromycin, potentially more pronounced in elderly patients.

CYP3A4 inhibitor that increases oxycodone plasma concentration, resulting in increased or prolonged opioid effects including respiratory depression and sedation.

CYP3A4 inhibitor that increases plasma concentration of oxycodone, resulting in increased or prolonged opioid effects and potential respiratory depression.

CYP3A4 inhibitor that increases oxycodone plasma concentration, resulting in increased or prolonged opioid effects including respiratory depression and sedation.

CYP3A4 inhibitor that increases oxycodone plasma concentration, resulting in increased or prolonged opioid effects including respiratory depression and sedation.

CYP3A4 inhibitor that increases oxycodone plasma concentration, resulting in increased or prolonged opioid effects including respiratory depression and sedation.

Erythromycin significantly increases pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis. Do not exceed pitavastatin 1 mg once daily.

Erythromycin significantly increases pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis. Dose limitation to 1 mg once daily is recommended.

Erythromycin significantly increases pitavastatin exposure and increases the risk of myopathy and rhabdomyolysis. Dosage should not exceed 1 mg once daily.

Increased risk of myopathy and rhabdomyolysis. Pravastatin sodium dose should not exceed 40 mg once daily.

CYP3A4 inhibitor may increase codeine plasma concentrations and morphine levels, potentially causing fatal respiratory depression.

CYP3A4 inhibitor that increases propafenone plasma levels, potentially causing cardiac arrhythmias and proarrhythmia risk.

CYP3A4 inhibitor that increases quinine plasma levels. Concomitant administration should be avoided.

Combined P-gp and moderate CYP3A inhibitor. Should not be used in patients with CrCl 15 to <80 mL/min unless potential benefit justifies risk.

CYP3A4 and CYP1A2 inhibitor that increases roflumilast systemic exposure and may result in increased adverse reactions.

CYP3A4 inhibitor that increases sufentanil plasma concentration, resulting in increased or prolonged opioid effects and risk of respiratory depression.

CYP3A4 inhibitor that increases sufentanil plasma concentration, resulting in increased or prolonged opioid effects including respiratory depression and sedation.

Mild or Moderate CYP3A Inhibitors: Clotrimazole, antibiotics (e.g., erythromycin, fluconazole), calcium channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and omeprazole May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.11, 5.12)].

Erythromycin may increase serum theophylline levels, potentially causing toxicity. Concomitant theophylline may decrease erythromycin concentrations by approximately 35%, resulting in subtherapeutic erythromycin levels.

Macrolide antibiotic and CYP3A4 inhibitor that increases tolterodine plasma concentrations. Dose reduction to 1 mg twice daily recommended.

Antibiotic that prolongs QT interval; should be avoided with toremifene citrate or requires close monitoring.

Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St. Drug Interactions CYP2D6 and CYP3A4 inhibitors: Concomitant administration of CYP2D6 and/or CYP3A4 inhibitors (See CLINICAL PHARMACOLOGY—Pharmacokinetics ), such as quinidine, fluoxetine, paroxetine and amitriptyline (CYP2D6 inhibitors), and ketoconazole and erythromycin (CYP3A4 inhibitors), may reduce metabolic clearance of tramadol increasing the risk for serious adverse events including seizures and serotonin syndrome. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St.

Erythromycin decreases clearance of triazolam, increasing its pharmacologic effects.

Hypotension, bradyarrhythmias, and lactic acidosis observed with concomitant use. CYP3A4-metabolized calcium channel blocker.

CYP3A4 inhibitor causing elevation of verapamil plasma levels, resulting in hypotension and bradyarrhythmias.

Concomitant administration with vinblastine sulfate has been reported to cause enhanced toxicity.

P-glycoprotein inhibitor that increases afatinib exposure. Reduce GILOTRIF dose by 10 mg per day if not tolerated.

Weak CYP3A inhibitor may increase alprazolam concentrations. Avoid use and consider dose reduction.

7.6 Drugs and Other Substances Demonstrated to be CYP3A Inhibitors on the Basis of Clinical Studies Involving Benzodiazepines Metabolized Similarly to Alprazolam or on the Basis of In Vitro Studies with Alprazolam or Other Benzodiazepines Use caution during the coadministration of Alprazolam and the following: Available data from clinical studies of benzodiazepines other than alprazolam suggest a possible drug interaction between alprazolam and the following: diltiazem, isoniazid, macrolide antibiotics such as erythromycin and clarithromycin, and grapefruit juice.

Erythromycin inhibits theophylline clearance, resulting in increased serum theophylline concentrations requiring dose reduction.

May interfere with the bactericidal effect of ampicillin.

Ascorbic acid may decrease the activity of erythromycin. Standard monitoring of antibiotic efficacy is warranted.

Thiamine, riboflavin, pyridoxine, niacinamide, and ascorbic acid decrease the antibiotic activity of erythromycin.

Concomitant erythromycin could increase bexarotene plasma concentrations through CYP3A4 inhibition, though increases unlikely to cause adverse effects with gel formulations.

OATP1B1/1B3 inhibitor increases brincidofovir AUC and Cmax, may increase adverse reactions. Monitor for elevations in transaminases, bilirubin, diarrhea, or GI events.

CYP3A4 inhibitor increases buprenorphine plasma concentration, resulting in increased or prolonged opioid effects including respiratory depression and sedation.

CYP3A4 inhibitor increases buprenorphine plasma concentration, resulting in increased or prolonged opioid effects.

Macrolide CYP3A4 inhibitor that increases carbamazepine plasma levels. Close monitoring of carbamazepine levels and dosage adjustment may be required.

Erythromycin, a moderate inhibitor of cytochrome P450 3A4, had no effect on the pharmacokinetics of either des-ciclesonide or erythromycin following oral inhalation of ciclesonide [see Clinical Pharmacology ( 12.3 )] .

CYP2D6 or CYP3A4 inhibitor that can increase clozapine levels and lead to adverse reactions. Close monitoring and dose reduction may be necessary.

Moderate CYP3A4 Inhibitors amprenavir aprepitant diltiazem erythromycin fluconazole, fosamprenavir (prodrug of amprenavir) verapamil Significant increase in colchicine plasma concentration is anticipated.

CYP3A4 inhibitor may increase plasma concentrations of estrogens and may result in side effects.

Increases cyclosporine concentrations via CYP3A4 inhibition. Dosage adjustment essential.

No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (for example, erythromycin, fluconazole, diltiazem and verapamil) [see Dosage and Administration (2) and Clinical Pharmacology (12.3)] .

No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (for example, erythromycin, fluconazole, diltiazem and verapamil) [see Dosage and Administration ( 2 ) and Clinical Pharmacology ( 12.3 )] .

Co-administration resulted in increased plasma concentrations of desloratadine and 3-hydroxydesloratadine, but no clinically relevant changes in safety profile.

CYP 3A4 Inhibitors: Concomitant administration of dexamethasone with erythromycin, a moderate CYP 3A4 inhibitor, has the potential to result in increased plasma concentrations of dexamethasone. Co-administration with other drugs that are metabolized by CYP 3A4 (e.g., indinavir, erythromycin) may increase their clearance, resulting in decreased plasma concentration.

Erythromycin inhibits CYP 3A4, potentially resulting in increased plasma concentrations of dexamethasone.

CYP 3A4 Inhibitors: Concomitant administration of dexamethasone with erythromycin, a moderate CYP 3A4 inhibitor, has the potential to result in increased plasma concentrations of dexamethasone. Co-administration with other drugs that are metabolized by CYP 3A4 (e.g., indinavir, erythromycin) may increase their clearance, resulting in decreased plasma concentration.

Cytochrome P450 inhibitor that may inhibit the 25-hydroxylation of doxercalciferol and reduce formation of active moiety. Dose adjustment may be necessary.

Monitor for potentially increased dronabinol-related adverse reactions when dronabinol capsules are co-administered with inhibitors of CYP2C9 (e.g., amiodarone, fluconazole) and inhibitors of CYP3A4 enzymes (e.g., ketoconazole, itraconazole, clarithromycin, ritonavir, erythromycin, grapefruit juice).

Substances increasing the exposure of estrogens and progestins (enzyme inhibitors) Concomitant administration of moderate or strong CYP3A4 inhibitors such as azole antifungals (for example, ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (for example, clarithromycin, erythromycin), diltiazem, and grapefruit juice did increase the plasma concentrations of the estrogen or the progestin or both [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ].

Concomitant administration of moderate or strong CYP3A4 inhibitors such as azole antifungals (e.g., ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g., clarithromycin, erythromycin), diltiazem, and grapefruit juice can increase the plasma concentrations of the estrogen or the progestin or both.

Concomitant administration of moderate or strong CYP3A4 inhibitors such as azole antifungals (e.g., ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g., clarithromycin, erythromycin), diltiazem, and grapefruit juice can increase the plasma concentrations of the estrogen or the progestin or both.

Concomitant administration of moderate or strong CYP3A4 inhibitors such as azole antifungals (e.g., ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (e.g., clarithromycin, erythromycin), diltiazem, and grapefruit juice can increase the plasma concentrations of the estrogen or the progestin or both.

Examples of moderate CYP3A inhibitors include: fluconazole erythromycin Grapefruit Concomitant use of TRIKAFTA with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of elexacaftor, tezacaftor and ivacaftor; therefore, food or drink containing grapefruit should be avoided during treatment with TRIKAFTA [see Dosage and Administration (2.4) ] .

Erythromycin may interfere with biliary excretion, glucuronidation, and intestinal beta-glucuronidase of entacapone; caution should be exercised.

7 DRUG INTERACTIONS • CYP3A Inhibitors: In post-MI HFrEF patients, do not exceed 25 mg once daily when used with moderate CYP3A inhibitors (e.g., verapamil, erythromycin, saquinavir, fluconazole).

Drug Interactions Erythromycin administration in patients receiving 3-hydroxy-3-methylglutaryl-coenzyme A (HMG CoA) reductase inhibitors (statins) that are extensively metabolized by cytochrome P450 isoform 3A4 (e.g., lovastatin or simvastatin) has been reported to cause increased risk of myopathy, including rhabdomyolysis. Do not administer erythromycin with lovastatin or simvastatin (See CONTRAINDICATIONS ). Erythromycin use in patients who are receiving high doses of theophylline may be associated with an increase of serum theophylline levels and potential theophylline toxicity.

CYP3A4 inhibitor that may increase plasma concentrations of estradiol and may result in side effects.

CYP3A4 inhibitor may increase estradiol acetate plasma concentration and result in side effects.

CYP3A4 inhibitor that may increase plasma concentrations of estrogens and may result in adverse reactions.

CYP3A4 inhibitor that may increase plasma concentrations of estrogens and result in adverse reactions.

CYP3A4 inhibitor may increase plasma concentrations of estrogen or progestin, resulting in adverse reactions.

CYP3A4 inhibitor that may increase estradiol plasma concentrations and result in adverse reactions.

CYP3A4 inhibitor that may increase estradiol plasma concentrations and result in adverse reactions.

CYP3A4 inhibitor that may increase plasma concentrations of estradiol valerate and result in side effects.

[See Clinical Pharmacology (12.3).] Substances Increasing the Systemic Exposure of COCs (enzyme inhibitors): Concomitant administration of moderate or strong CYP3A4 inhibitors like azole antifungals (for example, ketoconazole, itraconazole, voriconazole, fluconazole), verapamil, macrolides (for example, clarithromycin, erythromycin), diltiazem, and grapefruit increase the serum concentrations of both estradiol and dienogest. In a multiple dose study investigating the effect of CYP3A4 inhibitors (ketoconazole and erythromycin) on Natazia, steady state estradiol and dienogest exposures were increased when co-administered with ketoconazole or erythromycin [see Clinical Pharmacology ( 12.3 )] .

CYP3A4 inhibitor that may increase plasma concentrations of estrogens and result in side effects.

CYP3A4 inhibitor may increase plasma concentrations of estrogens and result in side effects.

No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, diltiazem, verapamil and grapefruit juice).

QT prolonging drug with torsades de pointes risk. Monitor overnight with continuous ECG in medical facility during initiation.

Erythromycin Fluticasone Propionate In a multiple-dose drug interaction trial, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics. Salmeterol In a repeat-dose trial in 13 healthy subjects, concomitant administration of erythromycin (a moderate CYP3A4 inhibitor) and salmeterol inhalation aerosol resulted in a 40% increase in salmeterol C max at steady state (ratio with and without erythromycin 1.4 [90% CI: 0.96, 2.03], P = 0.12), a 3.6-beat/min increase in heart rate ([95% CI: 0.19, 7.03], P <0.04), a 5.8-msec increase in QTc interval ([95% CI: -6.14, 17.77], P = 0.34), and no change in plasma potassium.

Drug known to prolong QTc interval; caution advised when used with haloperidol decanoate due to risk of QT prolongation.

Drug known to prolong QTc interval; caution advised when used with haloperidol due to risk of QT prolongation.

CYP3A4 inhibitor may increase serum hydrocortisone concentrations and risk of adverse reactions; may require dose decrease.

Drug Interactions with Other Drugs that Affect Itraconazole Concentrations Concomitant Drug Within Class Prevention or Management Drug Interactions with Other Drugs that Increase Itraconazole Concentrations and May Increase Risk of Adverse Reactions Associated with Itraconazole Antibacterials Ciprofloxacin a Erythromycin a Clarithromycin a Monitor for adverse reactions.

Therefore, a reduction of the KALYDECO dosage is recommended for patients aged 6 months and older taking concomitant moderate CYP3A inhibitors, such as fluconazole and erythromycin.

AUC of active metabolite was not affected but AUC of losartan was increased by 30%.

Macrolide antibiotics cause significant decrease in corticosteroid clearance, potentially increasing corticosteroid plasma concentrations.

Erythromycin inhibits CYP3A4, potentially increasing plasma concentrations of corticosteroids.

Macrolide antibiotic that may cause a significant decrease in corticosteroid clearance, increasing corticosteroid levels.

P450-3A4 inhibitor may result in prolonged sedation. Reduces clearance of midazolam and approximately doubles half-life.

Cytochrome P450-3A4 Inhibitors Caution is advised when Midazolam Injection is administered concomitantly with drugs that are known to inhibit the P450-3A4 enzyme system (e.g., cimetidine, erythromycin, diltiazem, verapamil, ketoconazole, and itraconazole).

CYP3A4 inhibitor that may increase mifepristone serum concentrations. Use with caution in patients currently or recently treated.

Caution should be exercised when coadministering mirtazapine with potent CYP3A4 inhibitors, HIV protease inhibitors, azole antifungals, erythromycin, or nefazodone.

Thiamine, riboflavin, pyridoxine, niacinamide, and ascorbic acid decrease erythromycin antibiotic activity.

Moderate (e.g., fluconazole, atazanavir, aprepitant, diltiazem, erythromycin) and Strong (e.g., itraconazole, ketoconazole, clarithromycin, ritonavir, saquinavir) CYP3A Inhibitors Clinical Impact Increase in plasma naldemedine concentrations [see Clinical Pharmacology (12.3) ] Intervention Monitor for potential naldemedine-related adverse reactions [see Adverse Reactions (6.1) ] .

Moderate and weak CYP3A4 inhibitors include alprozalam, ameprenavir, amiodarone, aprepitant, atazanavir, cimetidine, cyclosporine, diltiazem, erythromycin, fluconazole, fluoxetine, isoniazid, oral contraceptives, quinuprestin/dalfopristin, valproic acid, and verapamil.

P-gp and CYP3A4 inhibitor that may increase nintedanib exposure. Monitor patients closely for tolerability.

CYP3A4 inhibitor may increase plasma concentration of estrogen or progestin and may result in adverse reactions.

CYP3A4 inhibitor (macrolide antibiotic) that increases oliceridine plasma concentration and prolonged opioid adverse reactions. Caution advised with possible less frequent dosing needed.

Macrolide antibiotic and CYP3A4 inhibitor may alter oxybutynin pharmacokinetic parameters (Cmax and AUC). Caution should be used when co-administered.

Macrolide antibiotic and CYP3A4 inhibitor that may alter oxybutynin mean pharmacokinetic parameters (Cmax and AUC). Caution should be used when co-administered.

CYP3A4 inhibitor may decrease clearance of oxycodone, leading to increased plasma concentrations and prolonged opioid effects.

Bacteriostatic antibacterial may antagonize the bactericidal effect of penicillin. Concurrent use should be avoided.

Erythromycin may antagonize the bactericidal effect of penicillin G benzathine by interfering with active bacterial growth necessary for penicillin's effect.

Bacteriostatic antibiotic may antagonize the bactericidal effect of penicillin. Concurrent use should be avoided.

May antagonize the bactericidal effect of penicillin. Concurrent use should be avoided, though clinical significance is not well-documented.

CYP3A inhibitor; concomitant use in patients with widespread and/or erythrodermic disease should be done with caution due to potential for increased pimecrolimus levels.

Concomitant administration of a Moderate CYP 3A inducer, such as efavirenz, should be avoided unless the benefit outweighs the risks [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3) .] 7.2 CYP450 Inhibitors Concomitant administration of drugs that decrease the activity of drug metabolizing liver enzymes (CYP450 inhibitors), for example, cimetidine, ketoconazole, itraconazole, erythromycin, and ritonavir may increase plasma concentrations of praziquantel.

induce barbiturates, phenytoin, carbamazepine, rifampin inhibit ketoconazole, itraconazole, ritonavir, indinavir, macrolide antibiotics such as erythromycin indinavir, erythromycin Ketoconazole Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.

7 DRUG INTERACTIONS Moderate CYP3A inhibitors (e.g., diltiazem, verapamil, erythromycin): Limit ranolazine to 500 mg twice daily. Moderate CYP3A Inhibitors Limit the dose of ranolazine to 500 mg twice daily in patients on moderate CYP3A inhibitors, including diltiazem, verapamil, erythromycin, fluconazole, and grapefruit juice or grapefruit-containing products [see Dosage and Administration (2.2) , Clinical Pharmacology (12.3) ].

Antibacterial agent that inhibits CYP3A4. Repaglinide dose reductions and increased glucose monitoring may be required.

7.2 Drugs Having No Clinically Important Interactions with PERSERIS Based on pharmacokinetic studies with oral risperidone, no dosage adjustment of PERSERIS is required when administered concomitantly with amitriptyline, cimetidine, ranitidine, clozapine, topiramate and moderate CYP3A4 inhibitors (erythromycin).

Concomitant administration with moderate CYP3A4 inhibitors (e.g., diltiazem, erythromycin, verapamil) may increase concentration of silodosin capsules.

The recommended dose of BELSOMRA is 5 mg in subjects receiving moderate CYP3A inhibitors (e.g., amprenavir, aprepitant, atazanavir, ciprofloxacin, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, imatinib, verapamil).

CYP3A4 inhibitor; concomitant use in patients with widespread and/or erythrodermic disease should be done with caution due to potential increased tacrolimus absorption.

Tamsulosin hydrochloride capsules should be used with caution in combination with moderate inhibitors of CYP3A4 (e.g., erythromycin), in combination with strong (e.g., paroxetine) or moderate (e.g., terbinafine) inhibitors of CYP2D6, or in patients known to be CYP2D6 poor metabolizers, particularly at a dose higher than 0.4 mg (e.g., 0.8 mg). The effects of concomitant administration of a moderate CYP3A4 inhibitor (e.g., erythromycin) on the pharmacokinetics of tamsulosin hydrochloride have not been evaluated [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

Examples of moderate CYP3A inhibitors include: fluconazole erythromycin Co-administration of SYMDEKO with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of tezacaftor and ivacaftor; therefore, food or drink containing grapefruit should be avoided during treatment with SYMDEKO [see Dosage and Administration (2.4) , Clinical Pharmacology (12.3) , and Patient Counseling Information (17) ] .

Erythromycin inhibits theophylline clearance, resulting in increased serum theophylline concentrations. Smaller theophylline doses required when initiating therapy.

CYP3A4 inhibitor causing elevation of verapamil plasma levels. Hypotension, bradyarrhythmias, and lactic acidosis reported with concurrent use.

Moderate CYP3A4 inhibitors Erythromycin (500 mg t.i.d.) produced a 4-fold increase in vardenafil AUC and a 3-fold increase in C max when co­ administered with vardenafil hydrochloride tablets 5 mg in healthy volunteers. It is recommended not to exceed a single 5 mg dose of vardenafil hydrochloride tablets in a 24-hour period when used in combination with erythromycin.

Erythromycin decreases zafirlukast plasma levels by approximately 40% due to decreased zafirlukast bioavailability.

No clinically significant interaction found.

Co-administration results in increased plasma concentrations of desloratadine but no clinically relevant changes in safety profile.

Pharmacokinetic interaction study with racemic cetirizine showed no interaction with erythromycin.

Erythromycin increased losartan AUC by 30% but had no clinically significant effect on active metabolite. No significant interaction.

Terazosin has been used concomitantly with erythromycin in at least 50 patients with no interactions observed.

Used concomitantly with terazosin in at least 50 patients with no interactions observed.

Erythromycin coadministration in healthy volunteers did not significantly change amlodipine systemic exposure.

Erythromycin co-administration in healthy volunteers did not significantly change amlodipine systemic exposure.

However, due to the partial involvement of CYP3A enzymes in the metabolic elimination of armodafinil, coadministration of potent inducers of CYP3A4/5 (e.g., carbamazepine, phenobarbital, rifampin) or inhibitors of CYP3A4/5 (e.g., ketoconazole, erythromycin) could alter the plasma concentrations of armodafinil.

Antibacterials (macrolide or ketolide antibiotics): clarithromycin erythromycin telithromycin ↑ atazanavir ↑ cobicistat ↑ clarithromycin ↑ erythromycin ↑ telithromycin Consider alternative antibiotics.

Examples: Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole. 40 mg SD 1.37 1.16 Diltiazem 240 mg QD , 28 days 40 mg SD 1.51 1.00 Erythromycin 500 mg QID Four times daily , 7 days 10 mg SD 1.33 1.38 Amlodipine 10 mg, single dose 80 mg SD 1.18 0.91 Cimetidine 300 mg QID , 2 weeks 10 mg QD for 2 weeks 1.00 0.89 Colestipol 10 g BID , 24 weeks 40 mg QD for 8 weeks NA 0.74 Ratio based on a single sample taken 8-16 h post dose.

Erythromycin In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with erythromycin (1.5 g/day for 4 days) increased plasma buspirone concentrations (5 fold increase in C max and 6 fold increase in AUC).

Cytochrome P450 (CYP 450) Interactions It is not known if the effects of Butorphanol Tartrate Nasal Spray are altered by concomitant medications that affect hepatic metabolism of drugs (CYP 450 inhibitors or inducers) (e.g., erythromycin, theophylline, etc.), but physicians should be alert to the possibility that a smaller initial dose and longer intervals between doses may be needed.

Antimycobacterials: Rifampin a Rifapentine ↓Cabotegravir ↓Rilpivirine Antimycobacterial: Rifabutin a ↓Cabotegravir ↔Rifabutin ↓Rilpivirine Glucocorticoid (systemic): Dexamethasone (more than a single-dose treatment) ↓Rilpivirine Herbal product: St John’s wort ( Hypericum perforatum ) ↓Rilpivirine Macrolide or ketolide antibiotics: Azithromycin Clarithromycin Erythromycin ↔Cabotegravir ↑Rilpivirine Macrolides are expected to increase concentrations of rilpivirine and are associated with a risk of Torsade de Pointes [see Warnings and Precautions ( 5.5 )] .

These include probenecid, cholestyramine, and some antibiotics (e.g., erythromycin, rifampicin, ampicillin and chloramphenicol).

In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.

Antibacterials (macrolide or ketolide antibiotics): clarithromycin erythromycin telithromycin ↑ clarithromycin ↑ erythromycin ↑ telithromycin ↑ cobicistat ↑ atazanavir ↑ darunavir Consider alternative antibiotics with concomitant use of TYBOST coadministered with atazanavir or darunavir.

Antibacterials: clarithromycin, erythromycin, telithromycin ↑ darunavir ↑ cobicistat ↑ antibacterial Consider alternative antibiotics with concomitant use of PREZCOBIX.

Antibacterials: clarithromycin, erythromycin, telithromycin ↑ darunavir ↑ cobicistat ↑ antibacterial Consider alternative antibiotics with concomitant use of SYMTUZA.

There have been spontaneous or published reports of CYP3A based interactions of erythromycin with cyclosporine, carbamazepine, tacrolimus, alfentanil, disopyramide, rifabutin, quinidine, methyl-prednisolone, cilostazol, vinblastine and bromocriptine.

Macrolide or ketolide antibiotics: Clarithromycin Erythromycin Telithromycin ↔Dolutegravir ↑Rilpivirine Where possible, consider alternatives, such as azithromycin.

Doxazosin tablets have been used with the following drugs or drug classes: 1) analgesic/anti-inflammatory (e.g., acetaminophen, aspirin, codeine and codeine combinations, ibuprofen, indomethacin); 2) antibiotics (e.g., erythromycin, trimethoprim and sulfamethoxazole, amoxicillin); 3) antihistamines (e.g., chlorpheniramine); 4) cardiovascular agents (e.g., atenolol, hydrochlorothiazide, propranolol); 5) corticosteroids; 6) gastrointestinal agents (e.g., antacids); 7) hypoglycemics and endocrine drugs; 8) sedatives and tranquilizers (e.g., diazepam); 9) cold and flu remedies.

Macrolide or Ketolide Antibiotics: clarithromycin erythromycin telithromycin ↑ RPV ↔ clarithromycin ↔ erythromycin ↔ telithromycin Where possible, alternatives such as azithromycin should be considered.

Macrolide or Ketolide Antibiotics: clarithromycin erythromycin telithromycin ↑­ RPV ↔ clarithromycin ↔ erythromycin ↔ telithromycin Where possible, alternatives such as azithromycin should be considered.

Macrolide or Ketolide Antibiotics: clarithromycin erythromycin telithromycin ↑ RPV ↔ clarithromycin ↔ erythromycin ↔ telithromycin Where possible, alternatives such as azithromycin should be considered.

Drug Interactions Theophylline Erythromycin use in patients who are receiving high doses of theophylline may be associated with an increase in serum theophylline levels and potential theophylline toxicity. In case of theophylline toxicity and/or elevated serum theophylline levels, the dose of theophylline should be reduced while the patient is receiving concomitant erythromycin therapy. There have been published reports suggesting that when oral erythromycin is given concurrently with theophylline there is a decrease in erythromycin serum concentrations of approximately 35%.

Effects of Erythromycin on Felbamate The coadministration of erythromycin (1000 mg/day) for 10 days did not alter the pharmacokinetic parameters of C max , C min , AUC, Cl/kg or T max at felbamate daily doses of 3000 or 3600 mg/day in 10 otherwise healthy subjects with epilepsy.

Drugs that May Prolong the QT Interval and/or Induce Bradycardia Coadministration of Fexinidazole Tablets with drugs known to block potassium channels (e.g., antiarrhythmics, neuroleptics, fluoroquinolones, imidazole and triazole antifungals, pentamidine) prolong the QT interval (e.g., antimalarials, phenothiazines, tricyclic antidepressants, terfenadine and astemizole, IV erythromycin, and quinolone antibacterial drugs) and/or induce bradycardia (such as β-blockers) should be avoided [see Warnings and Precautions (5.2) ] . CYP450 Inhibitors Examples (not fully inclusive): Clarithromycin, itraconazole, voriconazole, erythromycin, fluconazole Clinical Impact Multiple CYP450 enzymes are involved in the metabolism of fexinidazole to its pharmacologically active M1 and M2 metabolites.

These include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus).

These include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus).

Erythromycin In a multiple-dose drug interaction study, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics.

In postmarketing experience, erythromycin has been reported to decrease the clearance of triazolam and midazolam, and thus, may increase the pharmacologic effect of these benzodiazepines.

Based on known metabolic profiles, clinically significant drug interactions are not expected between lopinavir and ritonavir and dapsone, trimethoprim/sulfamethoxazole, azithromycin, erythromycin, or fluconazole.

7.7 Antibiotics Concomitant use of ORKAMBI may decrease the exposure of clarithromycin, erythromycin, and telithromycin, which may reduce the effectiveness of these antibiotics.

Hepatic Enzyme Inhibitors ( e.g., ketoconazole, macrolide antibiotics such as erythromycin and troleandomycin ): Drugs which inhibit cytochrome P450 3A4 have the potential to result in increased plasma concentrations of corticosteroids.

Hepatic Enzyme Inhibitors (e.g., ketoconazole, macrolide antibiotics such as erythromycin and troleandomycin): Drugs which inhibit cytochrome P450 3A4 have the potential to result in increased plasma concentrations of corticosteroids.

Anti-infective clarithromycin, erythromycin ↑ clarithromycin ↑ erythromycin Refer to the respective prescribing information for anti-infective dose adjustment.

These include: specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus).

There have been spontaneous or published reports of CYP3A based interactions of erythromycin with cyclosporine, carbamazepine, tacrolimus, alfentanil, disopyramide, rifabutin, quinidine, methyl-prednisolone, cilostazol, vinblastine and bromocriptine.

Co-administration of the prokinetic drug erythromycin with pregabalin extended-release tablets did not result in any clinically important changes in the pharmacokinetics of pregabalin extended-release tablets [see Clinical Pharmacology (12) ] .

Macrolide or ketolide antibiotics: azithromycin clarithromycin erythromycin ↑ rilpivirine ↔ azithromycin ↔ clarithromycin ↔ erythromycin Macrolides are expected to increase concentrations of rilpivirine and are associated with a risk of Torsade de Pointes [Warnings and Precautions (5.4) ] .

Macrolide or ketolide antibiotics: azithromycin clarithromycin erythromycin ↑ rilpivirine ↔ azithromycin ↔ clarithromycin ↔ erythromycin Macrolides are expected to increase concentrations of rilpivirine and are associated with a risk of Torsade de Pointes [Warnings and Precautions (5.4)].

E xamples: Specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus).

Examples: Specific antipsychotics (e.g., ziprasidone, iloperidone, chlorpromazine, mesoridazine, droperidol); specific antibiotics (e.g., erythromycin, gatifloxacin, moxifloxacin, sparfloxacin); Class 1A antiarrhythmic medications (e.g., quinidine, procainamide); Class III antiarrhythmics (e.g., amiodarone, sotalol); and others (e.g., pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus).

Although specific interactions have not been studied, other CYP3A4 inhibitors, such as erythromycin, itraconazole, and grapefruit juice, would likely increase tadalafil exposure.

Erythromycin co-administration in healthy volunteers did not significantly change amlodipine systemic exposure.

Examples Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g.

Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of tramadol hydrochloride and acetaminophen and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology (12.3) ] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol.

Examples: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of tramadol hydrochloride and acetaminophen and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol.

Table 2: Examples of CYP450 Interactions with Warfarin Enzyme Inhibitors Inducers CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 7.3 Drugs that Increase Bleeding Risk Examples of drugs known to increase the risk of bleeding are presented in Table 3.

Table 2: Examples of CYP450 Interactions with Warfarin Enzyme Inhibitors Inducers CYP2C9 amiodarone, capecitabine, cotrimoxazole, etravirine, fluconazole, fluvastatin, fluvoxamine, metronidazole, miconazole, oxandrolone, sulfinpyrazone, tigecycline, voriconazole, zafirlukast aprepitant, bosentan, carbamazepine, phenobarbital, rifampin CYP1A2 acyclovir, allopurinol, caffeine, cimetidine, ciprofloxacin, disulfiram, enoxacin, famotidine, fluvoxamine, methoxsalen, mexiletine, norfloxacin, oral contraceptives, phenylpropanolamine, propafenone, propranolol, terbinafine, thiabendazole, ticlopidine, verapamil, zileuton montelukast, moricizine, omeprazole, phenobarbital, phenytoin, cigarette smoking CYP3A4 alprazolam, amiodarone, amlodipine, amprenavir, aprepitant, atorvastatin, atazanavir, bicalutamide, cilostazol, cimetidine, ciprofloxacin, clarithromycin, conivaptan, cyclosporine, darunavir/ritonavir, diltiazem, erythromycin, fluconazole, fluoxetine, fluvoxamine, fosamprenavir, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, nilotinib, oral contraceptives, posaconazole, ranitidine, ranolazine, ritonavir, saquinavir, telithromycin, tipranavir, voriconazole, zileuton armodafinil, amprenavir, aprepitant, bosentan, carbamazepine, efavirenz, etravirine, modafinil, nafcillin, phenytoin, pioglitazone, prednisone, rifampin, rufinamide 7.3 Drugs that Increase Bleeding Risk Examples of drugs known to increase the risk of bleeding are presented in Table 3 .

Co-administration of single, oral doses of zaleplon with erythromycin (10 mg and 800 mg, respectively), a strong, selective CYP3A4 inhibitor, produced a 34% increase in zaleplon's maximal plasma concentrations and a 20% increase in the area under the plasma concentration time curve. The magnitude of interaction with multiple doses of erythromycin is unknown.