Clarithromycin

Strong CYP3A inhibitor is contraindicated with alprazolam due to profound effect on clearance, resulting in increased concentrations.

Concomitant use with strong CYP3A inhibitor is contraindicated due to profound effect on alprazolam clearance resulting in increased concentrations.

Gastroprokinetic Agents: Cisapride Contraindicated Cisapride : [See Contraindications (4.2) ] Lipid-lowering agents: Lomitapide Lovastatin Simvastatin Atorvastatin Pravastatin Fluvastatin Contraindicated Use With Caution No Dose Adjustment Lomitapide, Lovastatin, Simvastatin: Clarithromycin may increase the exposure of these drugs by inhibition of CYP3A metabolism, thereby increasing the risk of toxicities from these drugs [see Contraindications (4.5) and Warnings and Precautions (5.4) ] Atorvastatin, Pravastatin, Fluvastatin: [See Warnings and Precautions (5.4) ] Hypoglycemic Agents: Nateglinide Pioglitazone Repaglinide Rosiglitazone Insulin Use With Caution Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone : [See Warnings and Precautions (5.4) and Adverse Reactions (6.2) ] Insulin : [See Warnings and Precautions (5.4) and Adverse Reactions (6.2) ] Immunosuppressants: Cyclosporine Tacrolimus Use With Caution Cyclosporine : There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.

Fatal drug interactions reported when colchicine is administered with clarithromycin, a dual inhibitor of CYP3A4 and P-glycoprotein. Life-threatening or fatal colchicine toxicity can occur.

Strong CYP3A4 inhibitor causing significant increases in colchicine plasma levels.

Anticipated significant increase in saxagliptin plasma concentrations. Do not coadminister with dapagliflozin and saxagliptin.

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. Clarithromycin inhibits cytochrome P450 3A4, resulting in elevation of disopyramide plasma levels.

7.2 Effects of Other Drugs on Dronedarone Ketoconazole and Other Potent CYP3A Inhibitors Concomitant use of ketoconazole as well as other potent CYP3A inhibitors such as itraconazole, voriconazole, ritonavir, clarithromycin, and nefazodone is contraindicated because exposure to dronedarone is significantly increased [see Contraindications (4) , Clinical Pharmacology (12.3) ] .

voriconazole ↓ voriconazole ↑ efavirenz Coadministration of efavirenz, emtricitabine and tenofovir disoproxil fumarate with voriconazole is contraindicated [see Contraindications ( 4 )] because it may lead to reduced therapeutic effect of voriconazole and increased risk of EFV-associated adverse reactions Anti-infective: clarithromycin ↓ clarithromycin ↑ 14-OH metabolite Consider alternatives to macrolide antibiotics because of the risk of QT interval prolongation.

Combination Therapy with Clarithromycin and Amoxicillin Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Intervention: See Contraindications, Warnings and Precautions in prescribing information for clarithromycin.

Combination Therapy with Clarithromycin and Amoxicillin Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Intervention: See Contraindications, Warnings and Precautions in prescribing information for clarithromycin.

Combination Therapy with Clarithromycin and Amoxicillin Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Intervention: See Contraindications, Warnings and Precautions in prescribing information for clarithromycin.

Strong CYP3A4 inhibitor. Should not be coadministered with everolimus.

Strong CYP3A4 inhibitor; co-administration with everolimus is not recommended.

] 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.

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

Antifungals: Itraconazole Fluconazole Use With Caution No Dose Adjustment Itraconazole: Both clarithromycin and itraconazole are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when administered concomitantly (see also Itraconazole under “Drugs That Affect Clarithromycin” in the table below). Fluconazole: [see Pharmacokinetics (12.3) ] Anti-Gout Agents: Colchicine (in patients with renal or hepatic impairment) Colchicine (in patients with normal renal and hepatic function) Contraindicated Use With Caution Colchicine : Colchicine is a substrate for both CYP3A and the efflux transporter, P-glycoprotein (Pgp).

Strong CYP3A4 inhibitor may increase systemic corticosteroid effects of fluticasone propionate.

Strong CYP3A4 inhibitor may increase systemic corticosteroid and cardiovascular adverse effects when used with fluticasone propionate and salmeterol.

Gastroprokinetic Agents: Cisapride Contraindicated Cisapride : [See Contraindications (4.2) ] Lipid-lowering agents: Lomitapide Lovastatin Simvastatin Atorvastatin Pravastatin Fluvastatin Contraindicated Use With Caution No Dose Adjustment Lomitapide, Lovastatin, Simvastatin: Clarithromycin may increase the exposure of these drugs by inhibition of CYP3A metabolism, thereby increasing the risk of toxicities from these drugs [see Contraindications (4.5) and Warnings and Precautions (5.4) ] Atorvastatin, Pravastatin, Fluvastatin: [See Warnings and Precautions (5.4) ] Hypoglycemic Agents: Nateglinide Pioglitazone Repaglinide Rosiglitazone Insulin Use With Caution Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone : [See Warnings and Precautions (5.4) and Adverse Reactions (6.2) ] Insulin : [See Warnings and Precautions (5.4) and Adverse Reactions (6.2) ] Immunosuppressants: Cyclosporine Tacrolimus Use With Caution Cyclosporine : There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.

CYP3A4 inhibitor may increase systemic exposure to irinotecan or SN-38. Do not administer unless no therapeutic alternatives.

Strong CYP3A4 inhibitor that increases ivabradine plasma concentrations, exacerbating bradycardia and conduction disturbances.

Combination Therapy with Clarithromycin and Amoxicillin Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Intervention: • See Contraindications and Warnings and Precautions in prescribing information for clarithromycin.

Strong CYP3A inhibitor that increases lemborexant AUC and Cmax, increasing risk of adverse reactions. Concomitant use should be avoided.

Concomitant use is contraindicated due to increased risk of QT prolongation and torsades de pointes.

Concomitant use of strong CYP3A4 inhibitors (such as boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, tipranavir/ritonavir, voriconazole) with lomitapide is contraindicated.

Gastroprokinetic Agents: Cisapride Contraindicated Cisapride : [See Contraindications (4.2) ] Lipid-lowering agents: Lomitapide Lovastatin Simvastatin Atorvastatin Pravastatin Fluvastatin Contraindicated Use With Caution No Dose Adjustment Lomitapide, Lovastatin, Simvastatin: Clarithromycin may increase the exposure of these drugs by inhibition of CYP3A metabolism, thereby increasing the risk of toxicities from these drugs [see Contraindications (4.5) and Warnings and Precautions (5.4) ] Atorvastatin, Pravastatin, Fluvastatin: [See Warnings and Precautions (5.4) ] Hypoglycemic Agents: Nateglinide Pioglitazone Repaglinide Rosiglitazone Insulin Use With Caution Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone : [See Warnings and Precautions (5.4) and Adverse Reactions (6.2) ] Insulin : [See Warnings and Precautions (5.4) and Adverse Reactions (6.2) ] Immunosuppressants: Cyclosporine Tacrolimus Use With Caution Cyclosporine : There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.

Strong CYP3A4 inhibitor that increases lurasidone exposure; concomitant use is contraindicated.

Macrolide antibiotic and strong CYP 3A4 inhibitor; should not be co-administered due to risk of vasospasm leading to cerebral ischemia and/or ischemia of extremities.

Macrolide antibiotic and strong CYP 3A4 inhibitor; rare reports of serious adverse events with ergot alkaloids including vasospasm leading to cerebral ischemia and ischemia of extremities.

Strong CYP3A4 inhibitor that increases plasma naloxegol concentrations and risk of adverse reactions; use is contraindicated.

Combination Therapy with Clarithromycin and Amoxicillin Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Intervention: See Contraindications, Warnings and Precautions in prescribing information for clarithromycin.

7.4 Combination Therapy with Clarithromycin Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions due to drug interaction [ See Warnings and Precautions in prescribing information for clarithromycin]. Because of these drug interactions, clarithromycin is contraindicated for co-administration with certain drugs [ See Contraindications in prescribing information for clarithromycin.] 7.5 Clopidogrel Omeprazole is an inhibitor of CYP2C19 enzyme.

Combination Therapy with Clarithromycin and Amoxicillin Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Intervention: See Contraindications , Warnings and Precautions in prescribing information for clarithromycin.

Gastroprokinetic Agents: Cisapride Contraindicated Cisapride : [See Contraindications (4.2) ] Lipid-lowering agents: Lomitapide Lovastatin Simvastatin Atorvastatin Pravastatin Fluvastatin Contraindicated Use With Caution No Dose Adjustment Lomitapide, Lovastatin, Simvastatin: Clarithromycin may increase the exposure of these drugs by inhibition of CYP3A metabolism, thereby increasing the risk of toxicities from these drugs [see Contraindications (4.5) and Warnings and Precautions (5.4) ] Atorvastatin, Pravastatin, Fluvastatin: [See Warnings and Precautions (5.4) ] Hypoglycemic Agents: Nateglinide Pioglitazone Repaglinide Rosiglitazone Insulin Use With Caution Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone : [See Warnings and Precautions (5.4) and Adverse Reactions (6.2) ] Insulin : [See Warnings and Precautions (5.4) and Adverse Reactions (6.2) ] Immunosuppressants: Cyclosporine Tacrolimus Use With Caution Cyclosporine : There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.

Combination Therapy with Clarithromycin and Amoxicillin Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Intervention: See Contraindications and Warnings and Precautions in prescribing information for clarithromycin.

Combination Therapy with Clarithromycin and Amoxicillin Clinical Impact: Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and are contraindicated. Intervention: See Contraindications and Warnings and Precautions in prescribing information for clarithromycin.

( 7.2 ) 7.1 Effects of Other Drugs on Ranolazine Strong CYP3A Inhibitors Do not use ranolazine with strong CYP3A inhibitors, including ketoconazole, itraconazole, clarithromycin, nefazodone, nelfinavir, ritonavir, indinavir, and saquinavir [see Contraindications (4) , Clinical Pharmacology (12.3) ].

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

This effect may reduce the efficacy of standard doses of such drugs, which include itraconazole, clarithromycin, and saquinavir. Therefore, carefully monitor for rifabutin associated adverse events in those patients also receiving CYP3A inhibitors, which include fluconazole and clarithromycin. Voriconazole 400 mg twice a day for 7 days (maintenance dose) 300 mg once a day for 7 days Healthy male subjects (12) ↑ AUC by 331%, ↑ C max by 195% ↑ AUC by ~100%, ↑ C max by ~100% g CONTRAINDICATED ANTI-PCP (Pneumocystis carinii pneumonia) Dapsone 50 mg once a day 300 mg once a day HIV infected patients (16) ND ↓ AUC by 27 -40% Sulfamethoxazole-Trimethoprim 800/160 mg 300 mg once a day HIV infected patients (12) ↓ AUC by 15-20% ANTI-MAC (Mycobacterium avium intracellulare complex) Azithromycin 500 mg once a day for 1 day, then 250 mg once a day for 9 days 300 mg once a day Healthy subjects (6) Clarithromycin 500 mg twice a day 300 mg once a day HIV infected patients (12) ↑ AUC by 75% ↓ AUC by 50% Monitor for rifabutin associated adverse events.

Gastroprokinetic Agents: Cisapride Contraindicated Cisapride : [See Contraindications (4.2) ] Lipid-lowering agents: Lomitapide Lovastatin Simvastatin Atorvastatin Pravastatin Fluvastatin Contraindicated Use With Caution No Dose Adjustment Lomitapide, Lovastatin, Simvastatin: Clarithromycin may increase the exposure of these drugs by inhibition of CYP3A metabolism, thereby increasing the risk of toxicities from these drugs [see Contraindications (4.5) and Warnings and Precautions (5.4) ] Atorvastatin, Pravastatin, Fluvastatin: [See Warnings and Precautions (5.4) ] Hypoglycemic Agents: Nateglinide Pioglitazone Repaglinide Rosiglitazone Insulin Use With Caution Nateglinide, Pioglitazone, Repaglinide, Rosiglitazone : [See Warnings and Precautions (5.4) and Adverse Reactions (6.2) ] Insulin : [See Warnings and Precautions (5.4) and Adverse Reactions (6.2) ] Immunosuppressants: Cyclosporine Tacrolimus Use With Caution Cyclosporine : There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with cyclosporine.

Strong CYP3A inhibitor; concomitant use not recommended due to increased suvorexant exposure.

Concomitant administration is contraindicated. Clarithromycin increases plasma concentrations of terfenadine's active acid metabolite threefold.

Strong CYP3A inhibitor that substantially increases ticagrelor exposure, increasing risk of dyspnea, bleeding, and other adverse events.

Strong CYP3A4 inhibitor. Should not be used with ubrogepant due to increased exposure risk.

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 )] .

Co-administration of LUPKYNIS with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) is contraindicated [see Contraindications ( 4 )] .

Combination Therapy with Clarithromycin and/or Amoxicillin Clinical Effect Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions, including potentially fatal arrhythmias, and is contraindicated. Prevention or Management See Contraindications and Warnings and Precautions in the prescribing information for clarithromycin.

Strong CYP3A4 inhibitor that may increase DM1 exposure and toxicity. Concomitant use should be avoided or KADCYLA treatment delayed.

Antiarrhythmic affected by clarithromycin CYP3A inhibition. Risk of QTc prolongation and arrhythmias.

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) . Atorvastatin The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP3A4 inhibitors (e.g., clarithromycin, HIV and HCV protease inhibitors, and itraconazole) [see Warnings and Precautions (5.1) and Clinical Pharmacology ( 12.3 ) ]. Intervention: In patients taking clarithromycin or itraconazole, do not exceed atorvastatin 20 mg [ see Dosage and Administration ( 2 )].

Strong CYP3A inhibitor may increase amlodipine plasma concentrations. Monitor for hypotension and edema; dose reduction may be needed.

( 7.3 ) 7.1 Drugs that Prolong QT Avoid use of anagrelide in patients taking medications that may prolong QT interval (including, but not limited to, chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, amiodarone, disopyramide, procainamide, and pimozide) [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2) ] .

( 7.3 ) 7.1 Drugs that Prolong QT Avoid use of AGRYLIN in patients taking medications that may prolong QT interval (including, but not limited to, chloroquine, clarithromycin, haloperidol, methadone, moxifloxacin, amiodarone, disopyramide, procainamide, and pimozide) [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.2) ] .

Intervention Avoid concomitant use of aprepitant Examples Moderate inhibitor: diltiazem Strong inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir Strong CYP3A4 Inducers Clinical Impact Substantially decreased exposure of aprepitant in patients chronically taking a strong CYP3A4 inducer may decrease the efficacy of aprepitant [see Clinical Pharmacology ( 12.3 )].

Strong CYP3A4 inhibitor increases aripiprazole exposure. Reduce aripiprazole dosage.

Strong CYP3A4 inhibitor that increases aripiprazole exposure. Avoid concomitant use because dosage cannot be modified.

7 DRUG INTERACTIONS The risk of myopathy during treatment with statins is increased with concurrent administration of fibric acid derivatives, lipid-modifying doses of niacin, cyclosporine, or strong CYP 3A4 inhibitors (e.g., clarithromycin, HIV protease inhibitors, and itraconazole) [ see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 ) ]. Drug Interactions Associated with Increased Risk of Myopathy/Rhabdomyolysis ( 2.6 , 5.1 , 7 , 12.3 ) Interacting Agents Prescribing Recommendations Cyclosporine, HIV protease inhibitors (tipranavir plus ritonavir), hepatitis C protease inhibitor (telaprevir) Avoid atorvastatin HIV protease inhibitor (lopinavir plus ritonavir) Use with caution and lowest dose necessary Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir plus ritonavir, darunavir plus ritonavir, fosamprenavir, fosamprenavir plus ritonavir) Do not exceed 20 mg atorvastatin daily HIV protease inhibitor (nelfinavir) Hepatitis C protease inhibitor (boceprevir) Do not exceed 40 mg atorvastatin daily • 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. Clarithromycin Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 80 mg with clarithromycin (500 mg twice daily) compared to that of atorvastatin calcium alone [ see Clinical Pharmacology ( 12.3 ) ].

Strong CYP3A4 inhibitor may increase corticosteroid exposure and risk of systemic side effects; monitor closely.

Strong CYP3A inhibitor may increase plasma concentrations of cabazitaxel. Avoid coadministration or consider 25% dose reduction.

Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) while taking COMETRIQ or reduce the dosage of COMETRIQ if concomitant use with strong CYP3A4 inhibitors cannot be avoided [see Dosage and Administration ( 2.2 ), Clinical Pharmacology ( 12.3 )] .

Darifenacin systemic exposure is increased with potent CYP3A4 inhibitors; daily dose should not exceed 7.5 mg when co-administered with clarithromycin.

Strong CYP3A4 inhibitor increases 21-desDFZ exposure 3-fold; reduce EMFLAZA dose to one third of recommended dosage.

Elevated digoxin serum concentrations reported with concomitant clarithromycin use, including cases of digoxin toxicity with potentially fatal arrhythmias.

Postmarketing reports of torsades de pointes with concurrent use. CYP3A-based interaction may increase disopyramide concentrations. Hypoglycemia reported with concomitant administration.

Antiarrhythmic with narrow safety margin; subject to CYP3A inhibition by clarithromycin, which may increase concentrations and prolong therapeutic/adverse effects.

Strong CYP3A inhibitor expected to significantly increase TRIKAFTA component exposures. TRIKAFTA dosage reduction required.

Avoid co-administering erlotinib with strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit or grapefruit juice) or a combined CYP3A4 and CYP1A2 inhibitor (e.g., ciprofloxacin).

Avoid co-administering erlotinib tablets with strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telithromycin, voriconazole, grapefruit or grapefruit juice) or a combined CYP3A4 and CYP1A2 inhibitor (e.g., ciprofloxacin).

Drug interaction studies have shown that esomeprazole does not have any clinically significant interactions with phenytoin, quinidine, clarithromycin, or amoxicillin. 7.6 Combination Therapy with Clarithromycin Coadministration of esomeprazole, clarithromycin, and amoxicillin has resulted in increases in the plasma levels of esomeprazole and 14-hydroxyclarithromycin [ see Clinical Pharmacology (12.4) ]. Concomitant administration of clarithromycin with other drugs can lead to serious adverse reactions due to drug interactions [ see Warnings and Precautions in prescribing information for clarithromycin ].

Strong CYP3A4 inhibitor expected to increase eszopiclone exposure and effects similarly to ketoconazole. Dose reduction needed.

Strong CYP3A4 inhibitor. Doses of fesoterodine greater than 4 mg not recommended in adult patients taking this drug.

Intervention Avoid concomitant use of fosaprepitant Examples Moderate inhibitor: diltiazemStrong inhibitors:ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir Strong CYP3A4Inducers Clinical Impact Substantially decreased exposure of aprepitant in patients chronically taking a strong CYP3A4 inducer may decrease the efficacy of fosaprepitant [see Clinical Pharmacology (12.3) ] .

Intervention Avoid concomitant use of FOCINVEZ Examples Moderate inhibitor: diltiazem Strong inhibitors: ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, nelfinavir Strong CYP3A4 Inducers Clinical Impact Substantially decreased exposure of aprepitant in patients chronically taking a strong CYP3A4 inducer may decrease the efficacy of FOCINVEZ [see Clinical Pharmacology (12.3)] .

Strong CYP3A4 inhibitor. Recommended maximum dosage of istradefylline is 20 mg once daily with concomitant use.

Itraconazole increases clarithromycin concentrations. Monitor for adverse reactions; concomitant drug dose reduction may be necessary.

Strong CYP3A inhibitor. Dosage reduction recommended for patients ≥6 months; not recommended for patients <6 months.

Strong CYP3A4 inhibitor may cause increased plasma concentration of triamcinolone acetonide and adverse reactions.

Strong CYP3A4 inhibitor may increase plasma concentration of triamcinolone leading to adverse reactions.

Strong CYP3A4 inhibitor that significantly decreases midazolam plasma clearance, resulting in prolonged sedation.

Strong CYP3A inhibitor may increase mifepristone plasma concentrations; limit mifepristone dose to 900 mg per day when used together.

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

Strong CYP3A4 inhibitor that significantly increases nimodipine plasma concentration and blood pressure lowering effect. Concomitant administration should generally be avoided.

Strong CYP3A4 inhibitor may increase osilodrostat concentration and risk of adverse reactions. Dose reduction by half recommended.

Avoid concomitant use of strong CYP3A inhibitors (e.g., clarithromycin, indinavir, itraconazole, ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole).

Strong CYP3A inhibitor increases paricalcitol exposure. Dose adjustment may be necessary; monitor intact PTH and serum calcium closely.

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

Antiarrhythmic affected by clarithromycin CYP3A inhibition. Increased concentrations may elevate risk of adverse effects.

Postmarketing reports of torsades de pointes occurring with concurrent use of clarithromycin and quinidine. CYP3A-based interaction increases serum concentrations.

Strong CYP3A4 inhibitor that increases regorafenib plasma concentrations and may lead to increased toxicity.

Decrease AUC by 56% Narcotic Analgesics Oxycodone Decrease AUC by 86% Morphine Decrease exposure Selective 5-HT3 Receptor Antagonists Ondansetron Decrease exposure Statins Metabolized by CYP3A4 Simvastatin Decrease exposure Thiazolidinediones Rosiglitazone Decrease AUC by 66% Tricyclic Antidepressants Nortriptyline i Decrease exposure Other Drugs Enalapril Decrease active metabolite exposure Chloramphenicol j Decrease exposure Clarithromycin Decrease exposure Dapsone Decrease exposure Doxycycline k Decrease exposure Irinotecan l Prevention or Management: Avoid the use of rifampin, strong CYP3A4 inducer, if possible.

Strong CYP3A4 inhibitor may increase salmeterol exposure and risk of cardiovascular effects.

Strong CYP3A4/5 inhibitor anticipated to significantly increase saxagliptin plasma concentrations. Limit saxagliptin dosage to 2.5 mg.

Strong CYP3A4/5 inhibitor anticipated to significantly increase saxagliptin plasma concentrations. Dose limitation required.

Antiarrhythmic affected by clarithromycin CYP3A inhibition. Risk of QTc prolongation and torsades de pointes.

Strong CYP3A Inhibitors 3 : Protease inhibitors (e.g, nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, letermovir, Schisandra sphenanthera extracts May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation).

Strong CYP3A Inhibitors : Protease inhibitors (e.g., nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone, letermovir, Schisandra sphenanthera extracts May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation).

( 7.1 ) 7.1 Effect of Other Drugs on TALZENNA Effect of P-gp Inhibitors Breast Cancer Avoid coadministration of TALZENNA with the following P-gp inhibitors: itraconazole, amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil.

Strong CYP3A inhibitor. Co-administration requires dosage adjustment of SYMDEKO.

Avoid coadministration of strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin, ritonavir) and strong CYP3A4 inducers (e.g., rifampin, phenytoin) with thiotepa due to the potential effects on efficacy and toxicity [see Clinical Pharmacology (12.2) ] . Avoid coadministration of strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin, ritonavir) and strong CYP3A4 inducers (e.g., rifampin, phenytoin) with thiotepa due to the potential effects on efficacy and toxicity [see Clinical Pharmacology (12.2) ] .

Potent CYP3A4 inhibitor that may increase tolterodine systemic exposure. Dose reduction to 2 mg once daily recommended.

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

Antibiotic and strong CYP3A4 inhibitor that prolongs QT interval; increases toremifene exposure and should be avoided.

Avoid using strong CYP3A inhibitors (e.g., oral ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, indinavir, lopinavir, ritonavir, boceprevir, nelfinavir, saquinavir, telaprevir, nefazodone, conivaptan) in patients taking YONDELIS.

Hypotension, bradyarrhythmias, and lactic acidosis observed with concurrent clarithromycin use.

Strong CYP3A4 inhibitor increases trazodone exposure, increasing risk of adverse reactions including cardiac arrhythmias. Consider lower trazodone dose.

Strong CYP3A4 inhibitor may increase triamcinolone plasma concentration and adverse reactions.

Concomitant administration may cause hypotension, bradyarrhythmias, and lactic acidosis.

Concomitant administration potentiates anticoagulant effects. Postmarketing reports suggest increased warfarin effect with clarithromycin.

CYP3A4 inhibitor that increases warfarin effect and INR; requires close monitoring.

Caution should be exercised when considering the co-administration of AIRSUPRA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions (5.11) ] .

Coadministration of alosetron and strong CYP3A4 inhibitors such as clarithromycin, telithromycin, protease inhibitors, voriconazole, and itraconazole has not been evaluated but should be undertaken with caution because of similar potential drug interactions.

Co-administration of alosetron and strong CYP3A4 inhibitors such as clarithromycin, telithromycin, protease inhibitors, voriconazole and itraconazole has not been evaluated but should be undertaken with caution because of similar potential drug interactions.

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.

Calcium Channel Blockers: Verapamil Amlodipine Diltiazem Nifedipine Use With Caution Verapamil : Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent verapamil, [see Warnings and Precautions (5.4) ] . Amlodipine, Diltiazem : [See Warnings and Precautions (5.4) ] Nifedipine : Nifedipine is a substrate for CYP3A.

Combined P-gp and strong CYP3A4 inhibitor, but pharmacokinetic data suggest no dose adjustment is necessary with concomitant apixaban administration.

Strong CYP3A4 inhibitor that increases aripiprazole exposure. Reduce aripiprazole dosage when used concomitantly.

Antivirals: Atazanavir Saquinavir (in patients with decreased renal function) Ritonavir Etravirine Maraviroc Boceprevir (in patients with normal renal function) Didanosine Zidovudine Use With Caution No Dose Adjustment Atazanavir : Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3) ] . Antivirals: Atazanavir Ritonavir (in patients with decreased renal function) Saquinavir (in patients with decreased renal function) Etravirine Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function) Use With Caution No Dose Adjustment Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3) ] . Since concentrations of 14-OH clarithromycin are significantly reduced when clarithromycin is co-administered with atazanavir, alternative antibacterial therapy should be considered for indications other than infections due to Mycobacterium avium complex.

Antivirals: Atazanavir Saquinavir (in patients with decreased renal function) Ritonavir Etravirine Maraviroc Boceprevir (in patients with normal renal function) Didanosine Zidovudine Use With Caution No Dose Adjustment Atazanavir : Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3) ] . Boceprevir: Both clarithromycin and boceprevir are substrates and inhibitors of CYP3A, potentially leading to a bi-directional drug interaction when co-administered.

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

Caution should be exercised when considering the co-administration of PULMICORT FLEXHALER with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions (5.7) ] .

Caution should be exercised when considering the coadministration of BREYNA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions (5.9) ] .

Caution should be exercised when considering the coadministration of budesonide inhalation suspension with long- term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions ( 5.12 ), Clinical Pharmacology ( 12.3 )].

CYP3A4 inhibitor may alter serum levels of calcifediol by inhibiting vitamin D metabolism enzymes. Dose adjustment and monitoring of serum 25-hydroxyvitamin D, PTH, and calcium may be required.

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

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

Increases cyclosporine concentrations via CYP3A4 inhibition. Dosage adjustment essential.

P-gp inhibitor that does not require dosage adjustment of dabigatran etexilate but increases exposure, especially with renal impairment.

Potent CYP3A4 inhibitor; darifenacin daily dose should not exceed 7.5 mg when co-administered.

Caution should be exercised when concomitantly administering CARDURA XL with a strong CYP 3A4 inhibitor, such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, or voriconazole [see Clinical Pharmacology (12.3) ] .

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.

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.

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.

Caution should be exercised when considering the coadministration of budesonide and formoterol fumarate dihydrate with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions (5.9) ] .

May potentiate hypoglycemic action of glyburide. Patient should be observed closely for hypoglycemia when administered and for loss of control when withdrawn.

May increase glucose-lowering effect of glimepiride, increasing susceptibility to and/or intensity of hypoglycemia.

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

Caution is recommended when administering imatinib mesylate tablets with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, and voriconazole).

Strong CYP3A4 inhibitor that increases levomilnacipran exposure. Maximum recommended dose is 80 mg once daily.

Triazolobenzodiazepines and Other Related Benzodiazepines: Midazolam Alprazolam Triazolam Temazepam Nitrazepam Lorazepam Use With Caution No Dose Adjustment Midazolam : When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3) ] . Temazepam, Nitrazepam, Lorazepam : For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.

Strong CYP3A inhibitor may increase ivacaftor exposure. Dosage adjustment recommended when initiating ORKAMBI.

John’s Wort Use With Caution There have been spontaneous or published reports of CYP3A based interactions of clarithromycin with alfentanil, methylprednisolone, cilostazol, bromocriptine, vinblastine, phenobarbital, and St.

Caution should be exercised when considering the co-administration of mometasone furoate nasal spray with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, cobicistat-containing products, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Clinical Pharmacology (12.3) ] .

Caution should be exercised when considering the coadministration of ASMANEX HFA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, cobicistat-containing products, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3) ] .

Caution should be exercised when considering the coadministration of DULERA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, cobicistat-containing products, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Warnings and Precautions (5.8) and Clinical Pharmacology (12.3) ] .

Caution should be exercised when considering the coadministration of mometasone furoate monohydrate nasal spray with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, cobicistat-containing products, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin) [see Clinical Pharmacology (12.3) ] .

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) ] .

Nevirapine significantly decreases clarithromycin exposure while increasing 14-OH metabolite concentrations, potentially reducing activity against Mycobacterium avium complex. Alternatives like azithromycin should be considered.

Triazolobenzodiazepines and Other Related Benzodiazepines: Midazolam Alprazolam Triazolam Temazepam Nitrazepam Lorazepam Use With Caution No Dose Adjustment Midazolam : When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3) ] . Temazepam, Nitrazepam, Lorazepam : For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.

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

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.

Caution should be exercised when paclitaxel is concomitantly administered with known substrates (e.g., midazolam, buspirone, felodipine, lovastatin, eletriptan, sildenafil, simvastatin, and triazolam), inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin), and inducers (e.g., rifampin and carbamazepine) of CYP3A4.

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

Rifapentine may increase metabolism and decrease activity. Dosage adjustment may be necessary.

Antivirals: Atazanavir Saquinavir (in patients with decreased renal function) Ritonavir Etravirine Maraviroc Boceprevir (in patients with normal renal function) Didanosine Zidovudine Use With Caution No Dose Adjustment Atazanavir : Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3) ] . Ritonavir, Etravirine: (see Ritonavir and Etravirine under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3) ] . Antivirals: Atazanavir Ritonavir (in patients with decreased renal function) Saquinavir (in patients with decreased renal function) Etravirine Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function) Use With Caution No Dose Adjustment Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3) ] .

Strong CYP3A4 inhibitor that may increase midostaurin concentrations and risk of toxicity. Monitor for increased adverse reactions, especially during first week of administration.

Antivirals: Atazanavir Saquinavir (in patients with decreased renal function) Ritonavir Etravirine Maraviroc Boceprevir (in patients with normal renal function) Didanosine Zidovudine Use With Caution No Dose Adjustment Atazanavir : Both clarithromycin and atazanavir are substrates and inhibitors of CYP3A, and there is evidence of a bi-directional drug interaction (see Atazanavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3) ] . Saquinavir : Both clarithromycin and saquinavir are substrates and inhibitors of CYP3A and there is evidence of a bi-directional drug interaction (see Saquinavir under “Drugs That Affect Clarithromycin” in the table below) [see Pharmacokinetics (12.3) ] . Antivirals: Atazanavir Ritonavir (in patients with decreased renal function) Saquinavir (in patients with decreased renal function) Etravirine Saquinavir (in patients with normal renal function) Ritonavir (in patients with normal renal function) Use With Caution No Dose Adjustment Atazanavir: When clarithromycin is co-administered with atazanavir, the dose of clarithromycin should be decreased by 50% [see Clinical Pharmacology (12.3) ] .

Triazolobenzodiazepines and Other Related Benzodiazepines: Midazolam Alprazolam Triazolam Temazepam Nitrazepam Lorazepam Use With Caution No Dose Adjustment Midazolam : When oral midazolam is co-administered with clarithromycin, dose adjustments may be necessary and possible prolongation and intensity of effect should be anticipated [see Warnings and Precautions (5.4) and Pharmacokinetics (12.3) ] . Temazepam, Nitrazepam, Lorazepam : For benzodiazepines which are not metabolized by CYP3A (e.g., temazepam, nitrazepam, lorazepam), a clinically important interaction with clarithromycin is unlikely.

Clarithromycin increases serum theophylline concentrations by approximately 20%. Monitoring of serum theophylline concentrations should be considered.

Alprazolam Triazolam Triazolam, Alprazolam: Caution and appropriate dose adjustments should be considered when triazolam or alprazolam is co-administered with clarithromycin. There have been postmarketing reports of drug interactions and central nervous system (CNS) effects (e.g., somnolence and confusion) with the concomitant use of clarithromycin and triazolam. 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.

Strong CYP3A4 inhibitor that increases upadacitinib exposure, may increase risk of adverse reactions. Dosage modification required based on indication.

Strong CYP3A4 inhibitor that increases vilazodone exposure; dose should not exceed 20 mg once daily.

Simultaneous oral administration may decrease steady-state zidovudine concentrations by 12% on average. When clarithromycin is given 2-4 hours prior to zidovudine, zidovudine Cmax increases 100%.

P-gp inhibitor that does not require dosage adjustment of PRADAXA.

CYP3A inhibitor not expected to have significant effect on prasugrel active metabolite pharmacokinetics.

Clarithromycin increases plasma ranitidine concentrations (57%), bismuth trough concentrations (48%), and 14-hydroxy-clarithromycin (31%). These effects are clinically insignificant.

Combined P-gp and strong CYP3A inhibitor, but pharmacokinetic data suggests no precautions necessary as exposure change unlikely to affect bleeding risk.

40% increase Clarithromycin Similar to erythromycin.

However, strong inhibitors of CYP3A (e.g., itraconazole, clarithromycin) may increase the plasma concentrations of amlodipine to a greater extent [see Drug Interactions (7) ] .

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

Macrolide antibiotics: clarithromycin ↑ clarithromycin ↓ 14-OH clarithromycin ↑ atazanavir Increased concentrations of clarithromycin may cause QTc prolongations; therefore, a dose reduction of clarithromycin by 50% should be considered when it is coadministered with atazanavir. In addition, concentrations of the active metabolite 14-OH clarithromycin are significantly reduced; consider alternative therapy for indications other than infections due to Mycobacterium avium complex. Coadministration of atazanavir with ritonavir and clarithromycin has not been studied.

Intervention: In patients taking clarithromycin or itraconazole, do not exceed ATORVALIQ 20 mg [see Dosage and Administration (2.5) ] . Examples: Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole. Saquinavir 400 mg BID /ritonavir 400 mg BID , 15 days 40 mg QD for 4 days 3.93 4.31 Elbasvir 50 mg QD /grazoprevir 200 mg QD , 13 days 10 mg SD 1.94 4.34 Simeprevir 150 mg QD , 10 days 40 mg SD 2.12 1.70 Clarithromycin 500 mg BID , 9 days 80 mg QD for 8 days 4.54 5.38 Darunavir 300 mg BID /ritonavir 100 mg BID , 9 days 10 mg QD for 4 days 3.45 2.25 Itraconazole 200 mg QD , 4 days 40 mg SD 3.32 1.20 Letermovir 480 mg QD , 10 days 20 mg SD 3.29 2.17 Fosamprenavir 700 mg BID /ritonavir 100 mg BID , 14 days 10 mg QD for 4 days 2.53 2.84 Fosamprenavir 1400 mg BID , 14 days 10 mg QD for 4 days 2.3 4.04 Nelfinavir 1250 mg BID , 14 days 10 mg QD for 28 days 1.74 2.22 Grapefruit Juice, 240 mL QD , Greater increases in AUC (ratio of AUC up to 2.5) and/or Cmax (ratio of Cmax up to 1.71) have been reported with excessive grapefruit consumption (≥ 750 mL-1.2 liters per day).

Other potent inhibitors of CYP3A4 (e.g., itraconazole, clarithromycin, nefazadone, ritonavir, saquinavir, nelfinavir, indinavir, atanazavir and telithromycin) would be expected to have similar effects.

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 )] .

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.

Antibacterial: clarithromycin ↔ darunavir ↑ clarithromycin No dose adjustment of the combination is required for patients with normal renal function. For co-administration of clarithromycin and darunavir/ritonavir in patients with renal impairment, the following dose adjustments should be considered: For subjects with CLcr of 30 mL/min to 60 mL/min, the dose of clarithromycin should be reduced by 50%. For subjects with CLcr of < 30 mL/min, the dose of clarithromycin should be reduced by 75%.

Antibacterial: clarithromycin ↔ darunavir ↑ clarithromycin No dose adjustment of the combination is required for patients with normal renal function. For co-administration of clarithromycin and darunavir/ritonavir in patients with renal impairment, the following dose adjustments should be considered: For subjects with CLcr of 30-60 mL/min, the dose of clarithromycin should be reduced by 50%. For subjects with CLcr of <30 mL/min, the dose of clarithromycin should be reduced by 75%.

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.

Co-administration with other drugs which strongly inhibit CYP 3A4 (e.g., itraconazole, clarithromycin, ritonavir, cobicistat-containing products) may lead to increased plasma concentrations of corticosteroids and potentially increase the risk for systemic corticosteroid side effects.

Co-administration with other drugs which strongly inhibit CYP 3A4 (e.g., itraconazole, clarithromycin, ritonavir, cobicistat-containing products) may lead to increased plasma concentrations of corticosteroids and potentially increase the risk for systemic corticosteroid side effects.

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

Anti-infective: Clarithromycin ↓ clarithromycin * ↑ 14-OH metabolite * Consider alternatives to macrolide antibiotics because of the risk of QT interval prolongation.

Anti-infective: Clarithromycin ↓clarithromycin* ­↑14-OH metabolite* Consider alternatives to macrolide antibiotics because of the risk of QT interval prolongation.

Antibacterials: clarithromycin telithromycin ↑ clarithromycin ↑ telithromycin ↑ cobicistat Patients with CL cr greater than or equal to 60 mL/minute: No dosage adjustment of clarithromycin is required. Patients with CL cr between 50 mL/minute and 60 mL/minute: The dosage of clarithromycin should be reduced by 50%.

Antibacterials: clarithromycin ↑ clarithromycin ↑ cobicistat Patients with CLcr greater than or equal to 60 mL/minute: No dose adjustment of clarithromycin is required. Patients with CLcr between 50 mL/minute and 60 mL/minute: The dose of clarithromycin should be reduced by 50%.

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.

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.

Antiinfective : clarithromycin ↑ etravirine ↓ clarithromycin ↑ 14-OH- clarithromycin Clarithromycin exposure was decreased by etravirine tablets; however, concentrations of the active metabolite, 14- hydroxy-clarithromycin, were increased. Because 14-hydroxy-clarithromycin has reduced activity against Mycobacterium avium complex (MAC), overall activity against this pathogen may be altered. Alternatives to clarithromycin, such as azithromycin, should be considered for the treatment of MAC.

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.

n % Change in Amprenavir Pharmacokinetic Parameters (90% CI) C max AUC C min Abacavir 300 mg twice daily for 2 to 3 weeks 900 mg twice daily for 2 to 3 weeks 4 ↔ ↔ ↔ Clarithromycin 500 mg twice daily for 4 days 1,200 mg twice daily for 4 days 12 ↑15 (↑1 to ↑31) ↑18 (↑8 to ↑29) ↑39 (↑31 to ↑47) Delavirdine 600 mg twice daily for 10 days 600 mg twice daily for 10 days 9 ↑40 Median percent change; confidence interval not reported. ↔ ↔ Clarithromycin 500 mg twice daily for 4 days 1,200 mg twice daily for 4 days 12 ↓10 (↓24 to ↑7) ↔ ↔ Delavirdine 600 mg twice daily for 10 days 600 mg twice daily for 10 days 9 ↓47 Median percent change; confidence interval not reported.

Drug Interactions No drug interaction studies have been conducted specifically with lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets. The following drug interactions are for the individual drug components: lansoprazole, amoxicillin, and clarithromycin. Therefore, the decision to adjust dosage should depend on the clinician’s assessment of among other things, the cumulative or net effect of the drug components of lansoprazole delayed-release capsules, amoxicillin capsules, and clarithromycin tablets.

Anti-infective: clarithromycin ↑ clarithromycin For patients with renal impairment, adjust clarithromycin dose as follows: For patients on KALETRA with CL CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients on KALETRA with CL CR < 30 mL/min the dose of clarithromycin should be decreased by 75%.

Co-administration of other strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, telithromycin, cobicistat-containing products) with triamcinolone acetonide injectable suspension may cause increased plasma concentration of triamcinolone leading to adverse reactions (see ADVERSE REACTIONS ).

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

The following are examples of medications that may increase the glucose-lowering effect of sulfonylureas including glimepiride, a component of pioglitazone and glimepiride tablets, increasing the susceptibility to and/or intensity of hypoglycemia: oral anti-diabetic medications, pramlintide acetate, insulin, angiotensin converting enzyme (ACE) inhibitors, H2 receptor antagonists, fibrates, propoxyphene, pentoxifylline, somatostatin analogs, anabolic steroids and androgens, cyclophosphamide, phenyramidol, guanethidine, fluconazole, sulfinpyrazone, tetracyclines, clarithromycin, disopyramide, quinolones, and those drugs that are highly protein-bound, such as fluoxetine, nonsteroidal anti-inflammatory drugs, salicylates, sulfonamides, chloramphenicol, coumarins, probenecid and monoamine oxidase inhibitors.

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)].

Anti-infective: clarithromycin ↑ clarithromycin For patients with renal impairment, adjust clarithromycin dose as follows: • For patients with CL CR 30 to 60 mL per min the dose of clarithromycin should be reduced by 50%. • For patients with CL CR less than 30 mL per min the dose of clarithromycin should be decreased by 75%.

40% increase Clarithromycin Similar to erythromycin.

Antimycobacterials: Clarithromycin ↑ Tipranavir, ↑ Clarithromycin, ↓ 14-hydroxy-clarithromycin metabolite No dose adjustment of APTIVUS or clarithromycin for patients with normal renal function is necessary. For patients with renal impairment the following dosage adjustments should be considered: For patients with CL CR 30 to 60 mL/min the dose of clarithromycin should be reduced by 50%. For patients with CL CR <30 mL/min the dose of clarithromycin should be decreased by 75%.