Itraconazole

7 DRUG INTERACTIONS Concomitant use of PDE5 inhibitors with alpha adrenergic antagonists, including alfuzosin hydrochloride extended-release tablets, can potentially cause symptomatic hypotension (5.4 , 7.4) 7.1 CYP3A4 Inhibitors Alfuzosin hydrochloride extended-release tablets are contraindicated for use with potent CYP3A4 inhibitors such as ketoconazole, itraconazole, or ritonavir, since alfuzosin blood levels are increased [see Contraindications (4) , Warnings and Precautions (5.4) and Clinical Pharmacology (12.3) ] .

Avoid coadministration of itraconazole with aliskiren due to significant interaction risk.

Avoid coadministration of itraconazole with aliskiren due to significant interaction risk.

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.

Coadministration is contraindicated. Itraconazole increases plasma concentrations, potentially increasing pharmacologic effects and adverse reactions.

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

Coadministration is contraindicated. Itraconazole increases plasma concentrations, potentially increasing pharmacologic effects and adverse reactions.

Coadministration is contraindicated in subjects with varying degrees of renal or hepatic impairment. Itraconazole increases plasma concentrations.

Strong CYP3A4 inhibitor causing significant increases in colchicine plasma levels.

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

Coadministration is contraindicated. Itraconazole increases plasma concentrations of ergot alkaloids, potentially increasing pharmacologic effects and adverse reactions.

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

Antiarrhythmics Disopyramide Dofetilide Dronedarone Quinidine a Contraindicated during and 2 weeks after itraconazole treatment.

Itraconazole increases dofetilide concentrations, potentially causing QT prolongation and Torsade de Pointes. Contraindicated during and 2 weeks after itraconazole treatment.

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) ] .

Coadministration is contraindicated in poor or intermediate CYP2D6 metabolizers and in subjects taking strong or moderate CYP2D6 inhibitors. Itraconazole increases plasma concentrations.

Coadministration is contraindicated. Itraconazole increases plasma concentrations, potentially increasing pharmacologic effects and adverse reactions.

Coadministration is contraindicated. Itraconazole increases plasma concentrations of ergot alkaloids, potentially increasing pharmacologic effects and adverse reactions.

Coadministration is contraindicated. Itraconazole increases plasma concentrations of ergot alkaloids, potentially increasing pharmacologic effects and adverse reactions.

Very potent CYP3A inhibitor; estazolam should be avoided in patients receiving itraconazole.

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.

Coadministration is contraindicated. Itraconazole increases plasma concentrations, potentially increasing pharmacologic effects and adverse reactions.

Coadministration is contraindicated in subjects with varying degrees of renal or hepatic impairment. Itraconazole increases plasma concentrations.

Co-administration is contraindicated; itraconazole increases plasma concentrations, potentially increasing pharmacologic effects and adverse reactions.

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

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.

Coadministration is contraindicated. Itraconazole increases plasma concentrations, potentially increasing pharmacologic effects and adverse reactions.

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

Coadministration is contraindicated. Itraconazole increases plasma concentrations, potentially increasing pharmacologic effects and adverse reactions.

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

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

Coadministration is contraindicated. Itraconazole increases plasma concentrations, potentially increasing pharmacologic effects and adverse reactions.

Coadministration is contraindicated. Itraconazole increases plasma concentrations, potentially increasing pharmacologic effects and adverse reactions.

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.

Lipid-Lowering Drugs Lomitapide Lovastatin a Simvastatin a Contraindicated during and 2 weeks after itraconazole treatment.

Coadministration is contraindicated. Itraconazole increases plasma concentrations, potentially increasing pharmacologic effects and adverse reactions.

Strong CYP3A4 inhibitor that increases exposure to both macitentan and tadalafil. Avoid concomitant use.

Itraconazole increases methadone concentrations. Contraindicated during and 2 weeks after itraconazole treatment.

Coadministration is contraindicated. Itraconazole increases plasma concentrations of ergot alkaloids, potentially increasing pharmacologic effects and adverse reactions.

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

Antipsychotics, Anxiolytics and Hypnotics Alprazolam a Aripiprazole a Buspirone a Cariprazine Diazepam a Haloperidol a Midazolam (IV) a Quetiapine Ramelteon Risperidone a Suvorexant Monitor for adverse reactions. Lurasidone Midazolam (oral) a Pimozide Triazolam a Contraindicated during and 2 weeks after itraconazole treatment.

Coadministration is contraindicated. Itraconazole increases plasma concentrations, potentially increasing pharmacologic effects and adverse reactions.

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

Calcium Channel Blockers Felodipine a Nisoldipine Contraindicated during and 2 weeks after itraconazole treatment.

Coadministration is contraindicated. Increased plasma concentrations may lead to QT prolongation and ventricular tachyarrhythmias.

Itraconazole increases quinidine concentrations, potentially causing QT prolongation and Torsade de Pointes. Contraindicated during and 2 weeks after itraconazole treatment.

( 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.

Telaprevir Decrease AUC by 92% Systemic Hormonal Contraceptives Prevention or Management Advise patients to change to non-hormonal methods of birth control during rifampin therapy Estrogens Decrease exposure Progestins Anticonvulsants Phenytoin § Decrease exposure § Antiarrhythmics Disopyramide Decrease exposure Mexiletine Decrease exposure Quinidine Decrease exposure Propafenone Decrease AUC by 50% to 67% Tocainide Decrease exposure Antiestrogens Tamoxifen Decrease AUC by 86% Toremifene Decrease steady state concentrations of toremifene in serum Antithrombotic Agents Clopidogrel Prevention or Management Concomitant use of clopidogrel and rifampin should be discouraged Increase active metabolite exposure and risk of bleeding Ticagrelor Prevention or Management Avoid use Decrease exposure Antipsychotics Haloperidol Decrease plasma concentrations by 70% Lurasidone Prevention or Management: Concomitant use is contraindicated (See CONTRADICTIONS ) Decrease exposure Oral Anticoagulants Prevention or Management Perform prothrombin time daily or as frequently as necessary to establish and maintain the required dose of anticoagulant Warfarin Decrease exposure Antifungals Fluconazole Decrease AUC by 23% Itraconazole Prevention or Management Not recommended 2 weeks before and during itraconazole treatment Decrease exposure Ketoconazole Decrease exposure Beta-blockers Metoprolol Decrease exposure Propranolol Decrease exposure Benzodiazepines Diazepam *,¶ Decrease exposure Benzodiazepine-Related Drugs Zopiclone Decrease AUC by 82% Zolpidem Decrease AUC by 73% Calcium Channel Blockers ¶ Diltiazem Decrease exposure Nifedipine # Decrease exposure Verapamil Decrease exposure Corticosteroids Þ Prednisolone Decrease exposure Cardiac Glycosides Digoxin Prevention or Management Measure serum digoxin concentrations before initiating rifampin.

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. Stronger CYP3A4 inhibitors such as ketoconazole or itraconazole could be expected to have greater effects than seen with saquinavir. 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. Stronger CYP3A4 inhibitors such as ketoconazole or itraconazole could be expected to have greater effects than seen with saquinavir. 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) ].

Strong CYP3A4 inhibitor that may cause significant increase in silodosin plasma concentrations. Concomitant administration is contraindicated.

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.

Coadministration is contraindicated in subjects with varying degrees of renal or hepatic impairment. Itraconazole increases plasma concentrations.

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

Potent CYP3A inhibitor; avoid use of tadalafil in patients taking itraconazole.

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

Triazolam is contraindicated with ketoconzaole, itraconazole, nefazodone, and several HIV protease inhibitors.

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 is contraindicated in CLL/SLL patients during dose initiation and ramp-up phase due to increased risk of tumor lysis syndrome.

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

Strong CYP3A inhibitor increases acalabrutinib plasma concentrations, potentially resulting in increased toxicity. Avoid co-administration or interrupt acalabrutinib if short-term use needed.

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

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

Itraconazole increases alfuzosin concentrations, increasing risk of adverse reactions. Not recommended during and 2 weeks after itraconazole treatment.

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 to a greater extent. Monitor for hypotension and edema; dose reduction may be needed.

Itraconazole increases apixaban concentrations. Not recommended during and 2 weeks after itraconazole treatment.

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.

( 7.1 ) Itraconazole Oral Solution Containing Hydroxypropyl-β-cyclodextrin: Avoid concomitant use of SCEMBLIX at all recommended doses. Itraconazole Oral Solution Containing Hydroxypropyl-β-cyclodextrin Concomitant use of SCEMBLIX with itraconazole oral solution containing hydroxypropyl-β-cyclodextrin decreases asciminib C max and AUC, which may reduce SCEMBLIX efficacy [see Clinical Pharmacology (12.3)] . Avoid coadministration of SCEMBLIX at all recommended doses with itraconazole oral solution containing hydroxypropyl-β-cyclodextrin.

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. Itraconazole Atorvastatin AUC was significantly increased with concomitant administration of atorvastatin 40 mg and itraconazole 200 mg [ see Clinical Pharmacology ( 12.3 ) ].

Strong CYP3A4 enzyme inhibitor increases avacopan exposure. Reduce avacopan dose to 30 mg once daily.

Antineoplastics irinotecan axitinib, dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib bortezomib, busulphan, docetaxel, erlotinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with itraconazole may increase the risk of potentially fatal adverse events.

Itraconazole increases bedaquiline concentrations. Concomitant itraconazole not recommended for more than 2 weeks at any time during bedaquiline treatment.

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

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

Axitinib Bosutinib Cabazitaxel Cabozantinib Ceritinib Cobimetinib Crizotinib Dabrafenib Dasatinib Docetaxel Ibrutinib Lapatinib Nilotinib Olaparib Pazopanib Sunitinib Trabectedin Trastuzumab-emtansine Vinca alkaloids Avoid use during and 2 weeks after itraconazole treatment.

Itraconazole increases buprenorphine (IV and sublingual) concentrations. Monitor for adverse reactions; concomitant drug dose reduction may be necessary.

Reduced busulfan clearance when itraconazole administered concomitantly with high-dose busulfan, increasing risk of busulfan toxicity. Monitor for signs of toxicity.

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

Axitinib Bosutinib Cabazitaxel Cabozantinib Ceritinib Cobimetinib Crizotinib Dabrafenib Dasatinib Docetaxel Ibrutinib Lapatinib Nilotinib Olaparib Pazopanib Sunitinib Trabectedin Trastuzumab-emtansine Vinca alkaloids Avoid use during and 2 weeks after itraconazole treatment.

Potent CYP3A4 enzyme inducer that may decrease itraconazole bioavailability and efficacy. Avoid use 2 weeks before and during itraconazole treatment.

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

Axitinib Bosutinib Cabazitaxel Cabozantinib Ceritinib Cobimetinib Crizotinib Dabrafenib Dasatinib Docetaxel Ibrutinib Lapatinib Nilotinib Olaparib Pazopanib Sunitinib Trabectedin Trastuzumab-emtansine Vinca alkaloids Avoid use during and 2 weeks after itraconazole treatment.

Axitinib Bosutinib Cabazitaxel Cabozantinib Ceritinib Cobimetinib Crizotinib Dabrafenib Dasatinib Docetaxel Ibrutinib Lapatinib Nilotinib Olaparib Pazopanib Sunitinib Trabectedin Trastuzumab-emtansine Vinca alkaloids Avoid use during and 2 weeks after itraconazole treatment.

Antineoplastics irinotecan axitinib, dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib bortezomib, busulphan, docetaxel, erlotinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with itraconazole may increase the risk of potentially fatal adverse events.

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

Antineoplastics irinotecan axitinib, dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib bortezomib, busulphan, docetaxel, erlotinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with itraconazole may increase the risk of potentially fatal adverse events.

Increases digoxin serum concentration by 80%. Requires monitoring and dose reduction of 30-50%.

Potent CYP3A4 enzyme inducer that may decrease itraconazole bioavailability and efficacy. Avoid use 2 weeks before and during itraconazole treatment.

Strong CYP3A inhibitor increases elexacaftor AUC 2.8-fold and tezacaftor AUC 4.0-4.5-fold, ivacaftor AUC 15.6-fold. 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).

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

Famotidine reduces gastric acidity and may significantly reduce itraconazole absorption. See prescribing information for administration instructions.

Itraconazole increases fentanyl concentrations, increasing risk of adverse reactions including respiratory depression. Not recommended during and 2 weeks after itraconazole treatment.

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)] .

Combined with gemfibrozil, itraconazole resulted in synergistic increase of repaglinide AUC (19.4-fold) and plasma concentration (70.4-fold), prolonging hypoglycemic effects.

Antineoplastics irinotecan axitinib, dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib bortezomib, busulphan, docetaxel, erlotinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with itraconazole may increase the risk of potentially fatal adverse events.

Antineoplastics irinotecan axitinib, dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib bortezomib, busulphan, docetaxel, erlotinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with itraconazole may increase the risk of potentially fatal adverse events.

Potent CYP3A4 enzyme inducer that may decrease itraconazole bioavailability and efficacy. Avoid use 2 weeks before and during itraconazole treatment.

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

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.

Antineoplastics irinotecan axitinib, dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib bortezomib, busulphan, docetaxel, erlotinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with itraconazole may increase the risk of potentially fatal adverse events.

Strong CYP3A4 inhibitor that increases leniolisib exposure 2-fold. Concomitant use should be avoided.

CYP3A4 and P-glycoprotein inhibitor increases loperamide peak plasma concentration 2.9-fold and systemic exposure 3.8-fold, increasing risk for cardiac adverse reactions.

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

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

Mobocertinib Avoid use during and 2 weeks after itraconazole treatment.

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) ] . Strong CYP3A inducers (e.g., rifampin) : Decreased naldemedine concentrations; avoid concomitant use ( 7 ) Other opioid antagonists : Potential for additive effect and increased risk of opioid withdrawal; avoid concomitant use ( 7 ) Moderate (e.g., fluconazole) and strong (e.g., itraconazole) CYP3A4 inhibitors : Increased naldemedine concentrations; monitor for adverse reactions ( 7 ) P-gp inhibitors (e.g., cyclosporine) : Monitor for adverse reactions ( 7 )

Potent CYP3A4 enzyme inducer that may decrease itraconazole bioavailability and efficacy. Avoid use 2 weeks before and during itraconazole treatment.

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

Antineoplastics irinotecan axitinib, dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib bortezomib, busulphan, docetaxel, erlotinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with itraconazole may increase the risk of potentially fatal adverse events.

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

Fluconazole, posaconazole and itraconazole : Avoid concomitant use with TALICIA. Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact Omeprazole can alter the absorption of other drugs due to its effect of reducing intragastric acidity thereby increasing gastric pH.

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

Alpha Blockers tamsulosin Analgesics methadone alfentanil, buprenorphine IV and sublingual, fentanyl, oxycodone, sufentanil Methadone: The potential increase in plasma concentrations of methadone when coadministered with itraconazole may increase the risk of serious cardiovascular events including QTc prolongation and torsade de pointes .

( 7.3 ) 7.1 Agents That May Increase Palbociclib Plasma Concentrations Effect of CYP3A Inhibitors Coadministration of a strong CYP3A inhibitor (itraconazole) increased the plasma exposure of palbociclib in healthy subjects by 87%. 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.

Axitinib Bosutinib Cabazitaxel Cabozantinib Ceritinib Cobimetinib Crizotinib Dabrafenib Dasatinib Docetaxel Ibrutinib Lapatinib Nilotinib Olaparib Pazopanib Sunitinib Trabectedin Trastuzumab-emtansine Vinca alkaloids Avoid use during and 2 weeks after itraconazole treatment.

Potent CYP3A4 enzyme inducer that may decrease itraconazole bioavailability and efficacy. Avoid use 2 weeks before and during itraconazole treatment.

Potent CYP3A4 enzyme inducer that may decrease itraconazole bioavailability and efficacy. Avoid use 2 weeks before and during itraconazole treatment.

Antineoplastics irinotecan axitinib, dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib bortezomib, busulphan, docetaxel, erlotinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with itraconazole may increase the risk of potentially fatal adverse events.

CYP3A4 inhibitor increases quetiapine exposure; dose reduction of quetiapine necessary.

Potent CYP3A4 inhibitor that increases quetiapine exposure; dose adjustment necessary.

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

Itraconazole increases rifabutin concentrations. Not recommended 2 weeks before, during, and 2 weeks after itraconazole treatment.

Strong CYP/P-gp/BCRP inhibitor increases riociguat exposure and may result in hypotension. Consider starting dose of 0.5 mg three times daily and monitor for hypotension.

Itraconazole increases rivaroxaban concentrations. Not recommended during and 2 weeks after itraconazole treatment.

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.

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

Antineoplastics irinotecan axitinib, dabrafenib, dasatinib, ibrutinib, nilotinib, sunitinib bortezomib, busulphan, docetaxel, erlotinib, imatinib, ixabepilone, lapatinib, ponatinib, trimetrexate, vinca alkaloids Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with itraconazole may increase the risk of potentially fatal adverse events.

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.

Itraconazole increases tamsulosin concentrations, increasing risk of adverse reactions. Not recommended during and 2 weeks after itraconazole treatment.

Antibacterials telithromycin, in subjects with severe renal impairment or severe hepatic impairment rifabutin telithromycin Telithromycin: The potential increase in plasma concentrations of telithromycin in subjects with severe renal impairment or severe hepatic impairment, when coadministered with itraconazole may increase the risk of serious cardiovascular events including QT prolongation and torsade de pointes.

Strong CYP3A inhibitor. Increased tezacaftor exposure 4.0-fold and ivacaftor 15.6-fold; dosage adjustment required.

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.

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

Strong CYP3A4 inhibitor that increases toremifene steady-state concentration 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.

Axitinib Bosutinib Cabazitaxel Cabozantinib Ceritinib Cobimetinib Crizotinib Dabrafenib Dasatinib Docetaxel Ibrutinib Lapatinib Nilotinib Olaparib Pazopanib Sunitinib Trabectedin Trastuzumab-emtansine Vinca alkaloids Avoid use during and 2 weeks after itraconazole treatment.

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.

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

CYP3A inhibitor that causes earlier onset and/or increased severity of neuromuscular side effects when used with vincristine sulfate. Concomitant use should be avoided.

Itraconazole increases vorapaxar concentrations. Not recommended during and 2 weeks after itraconazole treatment.

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

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.

Reduces gastric acidity and impairs itraconazole absorption from capsules. Administer at least 1 hour before or 2 hours after itraconazole.

Reduce gastric acidity and impair itraconazole capsule absorption. Use with caution and monitor antifungal activity.

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

Strong CYP3A4 inhibitor resulting in significant increase in atogepant exposure; dosage adjustment to 10 mg once daily recommended.

Atorvastatin a Monitor for drug adverse reactions.

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

Bortezomib Brentuximab vedotin Busulfan a Erlotinib Gefitinib a Idelalisib Imatinib Ixabepilone Nintedanib Panobinostat Ponatinib Ruxolitinib Sonidegib Tretinoin (oral) Vandetanib a Monitor for adverse reactions.

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.

Strong CYP3A4 inhibitor may increase serum cinacalcet levels. Dose adjustment and monitoring of iPTH, serum phosphorous, and serum calcium required.

Strong CYP3A4 inhibitor may increase serum levels of cinacalcet. Dose adjustment and monitoring of iPTH, serum phosphorus, and serum calcium may be required.

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.

Potent CYP3A4 inhibitor expected to decrease clearance of citalopram.

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

Strong CYP3A4 inhibitor increases bazedoxifene exposure (40%) and conjugated estrogens exposure (5-9%), potentially increasing drug effects.

Increases cyclosporine concentrations via CYP3A4 inhibition. Dosage adjustment essential.

Antivirals Daclatasvir Indinavir a Maraviroc Monitor for adverse reactions.

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

Antifungals : itraconazole, isavuconazole, ketoconazole, posaconazole voriconazole ↑ darunavir ↑ itraconazole ↑ isavuconazole ↑ ketoconazole ↔ posaconazole ↓ voriconazole Monitor for increased darunavir/ritonavir and/or antifungal adverse events with concomitant use of these antifungals. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg with monitoring for increased antifungal adverse events.

Antifungals: itraconazole, isavuconazole, ketoconazole, posaconazole voriconazole ↑ darunavir ↑ itraconazole ↑ isavuconazole ↑ ketoconazole ↔ posaconazole ↓ voriconazole Monitor for increased darunavir/ritonavir and/or antifungal adverse events with concomitant use of these antifungals. When co-administration is required, the daily dose of ketoconazole or itraconazole should not exceed 200 mg with monitoring for increased antifungal adverse events.

amitriptyline, desipramine, imipramine, nortriptyline ↑ TCAs Other antidepressants: trazodone ↑ trazodone Antifungals: itraconazole, isavuconazole, ketoconazole, posaconazole ↑ darunavir ↑ cobicistat Monitor for increased darunavir or cobicistat and/or antifungal adverse reactions. ↑ itraconazole ↑ ketoconazole ↑ isavuconazole ↔ posaconazole Specific dosing recommendations are not available for co-administration with these antifungals. Monitor for increased itraconazole or ketoconazole adverse reactions.

Tricyclic Antidepressants (TCAs): e.g., amitriptyline, desipramine, imipramine, nortriptyline ↑ TCAs Other antidepressants: trazodone ↑ trazodone Antifungals: itraconazole, isavuconazole, ketoconazole, posaconazole ↑ darunavir ↑ cobicistat Monitor for increased darunavir or cobicistat and/or antifungal adverse reactions. ↑ itraconazole ↑ isavuconazole ↑ ketoconazole ↔ posaconazole (not studied) Specific dosing recommendations are not available for co-administration with these antifungals. Monitor for increased itraconazole or ketoconazole adverse reactions.

Cobicistat Elvitegravir (ritonavir-boosted) Ombitasvir/Paritaprevir/Ritonavir with or without Dasabuvir Ritonavir Saquinavir (unboosted) a Monitor for adverse reactions. Antivirals Cobicistat Darunavir (ritonavir-boosted) Elvitegravir (ritonavir-boosted) Fosamprenavir (ritonavir-boosted) Indinavira Ombitasvir/Paritaprevir/Ritonavir with or without Dasabuvir Ritonavir Saquinavir Monitor for adverse reactions. For, cobicistat, elvitegravir, indinavir, ombitasvir/paritaprevir/ ritonavir with or without dasabuvir, ritonavir, and saquinavir, see also Table 1.

CYP3A4 inhibitor that may increase plasma hormone concentrations of desogestrel and ethinyl estradiol.

Dexlansoprazole can reduce the absorption of itraconazole due to its effect on gastric pH.

Antipsychotics, Anxiolytics and Hypnotics Alprazolam a Aripiprazole a Buspirone a Cariprazine Diazepam a Haloperidol a Midazolam (IV) a Quetiapine Ramelteon Risperidone a Suvorexant Monitor for adverse reactions.

Strong or moderate CYP 3A inhibitors a Examples b : Ketoconazole, itraconazole, cimetidine Patients currently receiving diltiazem therapy should be carefully monitored for a change in pharmacological effect when initiating and discontinuing therapy with strong or moderate inhibitors of CYP3A4.

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.

Cobicistat Elvitegravir (ritonavir-boosted) Ombitasvir/Paritaprevir/Ritonavir with or without Dasabuvir Ritonavir Saquinavir (unboosted) a Monitor for adverse reactions. Antivirals Cobicistat Darunavir (ritonavir-boosted) Elvitegravir (ritonavir-boosted) Fosamprenavir (ritonavir-boosted) Indinavira Ombitasvir/Paritaprevir/Ritonavir with or without Dasabuvir Ritonavir Saquinavir Monitor for adverse reactions. For, cobicistat, elvitegravir, indinavir, ombitasvir/paritaprevir/ ritonavir with or without dasabuvir, ritonavir, and saquinavir, see also Table 1.

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.

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.

Substances increasing the plasma concentrations of HCs: Co-administration of certain HCs and strong or moderate CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase the serum concentrations of progestins, including etonogestrel.

Concomitant administration of strong or moderate CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma estrogen and/or progestin concentrations.

Concomitant administration of strong or moderate CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase plasma estrogen and/or progestin concentrations.

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) ] .

Antivirals Cobicistat Darunavir (ritonavir-boosted) Elvitegravir (ritonavir-boosted) Fosamprenavir (ritonavir-boosted) Indinavira Ombitasvir/Paritaprevir/Ritonavir with or without Dasabuvir Ritonavir Saquinavir Monitor for adverse reactions.

May increase phenytoin serum levels; monitoring of phenytoin levels recommended.

Bortezomib Brentuximab vedotin Busulfan a Erlotinib Gefitinib a Idelalisib Imatinib Ixabepilone Nintedanib Panobinostat Ponatinib Ruxolitinib Sonidegib Tretinoin (oral) Vandetanib a Monitor for adverse reactions.

Glecaprevir/pibrentasvir Monitor for adverse reactions.

CYP3A4 inhibitor that increases haloperidol plasma concentrations; monitor for increased adverse effects including QTc prolongation.

CYP3A4 inhibitor that increases haloperidol plasma concentrations, raising risk of adverse events including QTc prolongation.

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

CYP3A4 inhibitor may decrease metabolism of ifosfamide to its active alkylating metabolites, potentially decreasing effectiveness of ifosfamide treatment.

Antivirals Daclatasvir Indinavir a Maraviroc Monitor for adverse reactions. For indinavir, see also Table 2. Antivirals Cobicistat Darunavir (ritonavir-boosted) Elvitegravir (ritonavir-boosted) Fosamprenavir (ritonavir-boosted) Indinavira Ombitasvir/Paritaprevir/Ritonavir with or without Dasabuvir Ritonavir Saquinavir Monitor for adverse reactions.

Lansoprazole can reduce absorption due to its effect on reducing intragastric acidity.

Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact: Lansoprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity. Antifungals: Itraconazole Use With Caution 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 Tablets" in the table below). Clarithromycin may increase the plasma concentrations of itraconazole.

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

Itraconazole, a CYP3A4 inhibitor, may increase plasma hormone concentrations of COCs.

CYP3A4 inhibitor itraconazole may increase plasma hormone levels.

CYP3A4 inhibitor that may increase plasma hormone levels.

Aprepitant Loperamide a Monitor for adverse reactions.

Strong CYP3A inhibitor increases ivacaftor exposure 4.3-fold. Dosage adjustment needed when initiating ORKAMBI in patients taking itraconazole.

Suppress acid secretion and impair itraconazole capsule absorption. Use with caution and monitor antifungal activity.

Budesonide (inhalation) a Budesonide (non-inhalation) Ciclesonide (inhalation) Cyclosporine (IV) a Cyclosporine (non-IV) Dexamethasone a Fluticasone (inhalation) a Fluticasone (nasal) Methylprednisolone a Tacrolimus (IV) a Tacrolimus (oral) Monitor for adverse reactions.

7 DRUG INTERACTIONS Monitor for sirolimus, itraconazole or nifedipine toxicity and dosage of sirolimus, itraconazole or nifedipine should be reduced, if necessary. ( 7 ) 7.1 Effect of Other Drugs on Micafungin CYP3A4, CYP2C9 and CYP2C19 Inhibitors Co-administration of micafungin with cyclosporine, itraconazole, voriconazole and fluconazole did not alter the pharmacokinetics of micafungin. Itraconazole AUC and C max were increased by 22% and 11%, respectively.

7 DRUG INTERACTIONS Monitor for sirolimus, itraconazole or nifedipine toxicity, and dosage of sirolimus, itraconazole or nifedipine should be reduced, if necessary. ( 7 ) 7.1 Effect of Other Drugs on Micafungin CYP3A4, CYP2C9 and CYP2C19 Inhibitors Co-administration of micafungin with cyclosporine, itraconazole, voriconazole and fluconazole did not alter the pharmacokinetics of micafungin. Itraconazole AUC and C max were increased by 22% and 11%, respectively.

Other Drug Interactions Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the P450-3A4 enzyme system such as cimetidine (not ranitidine), erythromycin, diltiazem, verapamil, ketoconazole and itraconazole.

P450-3A4 inhibitor may result in prolonged sedation due to decreased plasma clearance of midazolam.

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).

Strong CYP3A inhibitor may increase mirtazapine plasma concentration. May require dose decrease.

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) ] .

Beta Blockers Nadolol a Monitor for adverse reactions.

Bortezomib Brentuximab vedotin Busulfan a Erlotinib Gefitinib a Idelalisib Imatinib Ixabepilone Nintedanib Panobinostat Ponatinib Ruxolitinib Sonidegib Tretinoin (oral) Vandetanib a Monitor for adverse reactions.

CYP3A4 inhibitor that may increase plasma hormone concentrations.

Substances increasing the systemic concentrations of HCs: Co-administration of certain HCs and strong or moderate CYP3A4 inhibitors such as itraconazole, voriconazole, fluconazole, grapefruit juice, or ketoconazole may increase the systemic concentrations of progestins, including norethindrone.

CYP3A4 inhibitor that may increase plasma hormone concentrations.

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

CYP3A4 inhibitor that may increase plasma hormone concentrations of norethindrone and ethinyl estradiol.

CYP3A4 inhibitor that may increase plasma hormone concentrations of ethinyl estradiol and norgestimate.

CYP3A4 inhibitor may increase plasma hormone concentrations.

Cobicistat Elvitegravir (ritonavir-boosted) Ombitasvir/Paritaprevir/Ritonavir with or without Dasabuvir Ritonavir Saquinavir (unboosted) a Monitor for adverse reactions. Antivirals Cobicistat Darunavir (ritonavir-boosted) Elvitegravir (ritonavir-boosted) Fosamprenavir (ritonavir-boosted) Indinavira Ombitasvir/Paritaprevir/Ritonavir with or without Dasabuvir Ritonavir Saquinavir Monitor for adverse reactions. For, cobicistat, elvitegravir, indinavir, ombitasvir/paritaprevir/ ritonavir with or without dasabuvir, ritonavir, and saquinavir, see also Table 1.

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

Antimycotic agent 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.

Cobicistat Elvitegravir (ritonavir-boosted) Ombitasvir/Paritaprevir/Ritonavir with or without Dasabuvir Ritonavir Saquinavir (unboosted) a Monitor for adverse reactions. Antivirals Cobicistat Darunavir (ritonavir-boosted) Elvitegravir (ritonavir-boosted) Fosamprenavir (ritonavir-boosted) Indinavira Ombitasvir/Paritaprevir/Ritonavir with or without Dasabuvir Ritonavir Saquinavir Monitor for adverse reactions. For, cobicistat, elvitegravir, indinavir, ombitasvir/paritaprevir/ ritonavir with or without dasabuvir, ritonavir, and saquinavir, see also Table 1.

May increase phenytoin serum levels; monitoring of phenytoin levels recommended.

Glecaprevir/pibrentasvir Monitor for adverse reactions.

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

Potent P450 3A4 inhibitor and p-glycoprotein inhibitor increased pravastatin AUC by 1.7-fold and Cmax by 2.5-fold.

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.

Rabeprazole may decrease absorption of itraconazole due to increased gastric pH.

Antifungal 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.

Cobicistat Elvitegravir (ritonavir-boosted) Ombitasvir/Paritaprevir/Ritonavir with or without Dasabuvir Ritonavir Saquinavir (unboosted) a Monitor for adverse reactions. Antivirals Cobicistat Darunavir (ritonavir-boosted) Elvitegravir (ritonavir-boosted) Fosamprenavir (ritonavir-boosted) Indinavira Ombitasvir/Paritaprevir/Ritonavir with or without Dasabuvir Ritonavir Saquinavir Monitor for adverse reactions. For, cobicistat, elvitegravir, indinavir, ombitasvir/paritaprevir/ ritonavir with or without dasabuvir, ritonavir, and saquinavir, see also Table 1.

Bortezomib Brentuximab vedotin Busulfan a Erlotinib Gefitinib a Idelalisib Imatinib Ixabepilone Nintedanib Panobinostat Ponatinib Ruxolitinib Sonidegib Tretinoin (oral) Vandetanib a Monitor for adverse reactions.

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

Cobicistat Elvitegravir (ritonavir-boosted) Ombitasvir/Paritaprevir/Ritonavir with or without Dasabuvir Ritonavir Saquinavir (unboosted) a Monitor for adverse reactions. Antivirals Cobicistat Darunavir (ritonavir-boosted) Elvitegravir (ritonavir-boosted) Fosamprenavir (ritonavir-boosted) Indinavira Ombitasvir/Paritaprevir/Ritonavir with or without Dasabuvir Ritonavir Saquinavir Monitor for adverse reactions. For, cobicistat, elvitegravir, indinavir, ombitasvir/paritaprevir/ ritonavir with or without dasabuvir, ritonavir, and saquinavir, see also Table 1.

CYP3A4 inhibitor that may increase systemic exposure of estrogen and/or progestin component.

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

Potent CYP3A4 inhibitor that may increase itraconazole bioavailability. Monitor for increased itraconazole exposure.

Tenofovir disoproxil fumarate Monitor for adverse reactions.

Agents for Opportunistic Infections Antifungals: Fluconazole Itraconazole Ketoconazole ↑ Tipranavir, ↔ Fluconazole Fluconazole increases tipranavir concentrations but dose adjustments are not needed. Voriconazole ↑ Itraconazole (not studied) ↑ Ketoconazole (not studied) Based on theoretical considerations itraconazole and ketoconazole should be used with caution.

CYP3A4 inhibitor increases plasma concentrations of ulipristal acetate.

Co-administration with itraconazole, a strong CYP3A4 inhibitor, increases vamorolone exposure. Dosage reduction of AGAMREE is required when used concomitantly.

Bortezomib Brentuximab vedotin Busulfan a Erlotinib Gefitinib a Idelalisib Imatinib Ixabepilone Nintedanib Panobinostat Ponatinib Ruxolitinib Sonidegib Tretinoin (oral) Vandetanib a Monitor for adverse reactions.

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

Bi-directional CYP3A interaction may increase clarithromycin exposure, increasing risk of adverse reactions; close monitoring recommended.

Itraconazole is a strong CYP2C9 inhibitor likely to increase zafirlukast exposure.

34% increase in zolpidem AUC with combination use.

No dose adjustment needed when co-administered with montelukast sodium.

No dose adjustment needed when co-administered with montelukast sodium.

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

Antifungals: ketoconazole, itraconazole REYATAZ with ritonavir: ↑ ketoconazole ↑ itraconazole Coadministration of ketoconazole has only been studied with REYATAZ without ritonavir (negligible increase in atazanavir AUC and C max ). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously when administering REYATAZ with ritonavir.

Tricyclic Antidepressants (TCAs) (e.g., amitriptyline, desipramine, imipramine, nortriptyline) ↑ TCAs Other Antidepressants (e.g., trazodone) ↑ trazodone Antifungals: ketoconazole, itraconazole ↑ atazanavir ↑ cobicistat ↑ ketoconazole ↑ itraconazole Specific dosing recommendations are not available for coadministration of EVOTAZ with either itraconazole or ketoconazole.

Antifungals: ketoconazole, itraconazole Atazanavir with ritonavir: ↑ ketoconazole ↑ itraconazole Coadministration of ketoconazole has only been studied with atazanavir without ritonavir (negligible increase in atazanavir AUC and C max ). Due to the effect of ritonavir on ketoconazole, high doses of ketoconazole and itraconazole (>200 mg/day) should be used cautiously when administering atazanavir with ritonavir.

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).

For Boceprevir, cobicistat, elvitegravir, indinavir, ombitasvir/paritaprevir/ritonavir with or without dasabuvir, ritonavir and saquinavir, see also Table 1.

Itraconazole In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with itraconazole (200 mg/day for 4 days) increased plasma buspirone concentrations (13 fold increase in C max and 19 fold increase in AUC).

Itraconazole: In a study in healthy volunteers, coadministration of buspirone (10 mg as a single dose) with itraconazole (200 mg/day for 4 days) increased plasma buspirone concentrations (13 fold increase in C max and 19 fold increase in AUC).

Axitinib Bosutinib Cabazitaxel Cabozantinib Ceritinib Cobimetinib a Crizotinib Dabrafenib Dasatinib Docetaxel Ibrutinib Lapatinib Nilotinib Olapariba Pazopanib Sunitinib Trabectedin Trastuzumab emtansine Vinca alkaloids Not recommended during and 2 weeks after itraconazole treatment.

Antifungals: itraconazole ketoconazole ↑ itraconazole ↑ ketoconazole Specific dosing recommendations are not available for coadministration with itraconazole or ketoconazole.

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.

Antifungals: itraconazole ↓ itraconazole ¯ hydroxy- itraconazole Since no dose recommendation for itraconazole can be made, alternative antifungal treatment should be considered.

Antifungals: Itraconazole Ketoconazole Posaconazole ↓itraconazole* ↓hydroxyitraconazole* ↓ketoconazole ↓posaconazole* Consider alternative antifungal treatment because no dose recommendation for itraconazole or ketoconazole can be made.

Elbasvir/grazoprevir Glecaprevir/pibrentasvir Tenofovir disoproxil fumarate Not recommended during and 2 weeks after itraconazole treatment.

Antifungals: itraconazole ketoconazole voriconazole ↑ elvitegravir ↑ cobicistat ↑ itraconazole ↑ ketoconazole ↑ voriconazole When administering with GENVOYA, the maximum daily dosage of ketoconazole or itraconazole should not exceed 200 mg per day.

Tricyclic Antidepressants (TCAs) e.g., amitriptyline desipramine imipramine nortriptyline bupropion trazodone Antifungals: itraconazole ketoconazole voriconazole ↑ elvitegravir ↑ cobicistat ↑ itraconazole ↑ ketoconazole ↑ voriconazole When coadministered with STRIBILD, the maximum daily dose of ketoconazole or itraconazole should not exceed 200 mg per day.

No clinically significant drug interactions have been either observed or are expected when DESCOVY is combined with the following drugs: buprenorphine, itraconazole, ketoconazole, lorazepam, methadone, midazolam, naloxone, norbuprenorphine, norgestimate/ethinyl estradiol, and sertraline.

Azole Antifungal Agents: fluconazole itraconazole ketoconazole posaconazole voriconazole ↑ RPV , This interaction study has been performed with a dose higher than the recommended dose for RPV assessing the maximal effect on the coadministered drug.

Azole Antifungal Agents: fluconazole itraconazole ketoconazole posaconazole voriconazole ↑ RPV , This interaction study has been performed with a dose higher than the recommended dose for RPV.

Azole Antifungal Agents: fluconazole itraconazole ketoconazole posaconazole voriconazole ↑ RPV , This interaction study has been performed with a dose higher than the recommended dose for RPV assessing the maximal effect on the coadministered drug.

Entrectinib Pemigatinib Talazoparib Refer to the entrectinib, pemigatinib and talazoparib prescribing information for dosing instructions if concomitant use cannot be avoided.

Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole ) Clinical Impact: Esomeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity Intervention: Mycophenolate mofetil (MMF): Co-administration of omeprazole, of which esomeprazole is an enantiomer, in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH.

Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact: Esomeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity Intervention: Mycophenolate mofetil (MMF): Co-administration of omeprazole, of which esomeprazole is an enantiomer, in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH.

Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact: Esomeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity Intervention: Mycophenolate mofetil (MMF): Co-administration of omeprazole, of which esomeprazole is an enantiomer, in healthy subjects and in transplant patients receiving MMF has been reported to reduce the exposure to the active metabolite, mycophenolic acid (MPA), possibly due to a decrease in MMF solubility at an increased gastric pH.

Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact: Esomeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.

Antifungals : itraconazole ketoconazole posaconazole ↑ etravirine ↓ itraconazole ↓ ketoconazole ↔ posaconazole Posaconazole, a potent inhibitor of CYP3A4, may increase plasma concentrations of etravirine. Itraconazole and ketoconazole are potent inhibitors as well as substrates of CYP3A4. Concomitant systemic use of itraconazole or ketoconazole and etravirine tablets may increase plasma concentrations of etravirine.

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.

Antifungals: Ketoconazole a , itraconazole ↑ Ketoconazole ↑ Itraconazole Increase monitoring for adverse events. Fosamprenavir calcium: Dose reduction of ketoconazole or itraconazole may be needed for patients receiving more than 400 mg ketoconazole or itraconazole per day. Fosamprenavir calcium/ritonavir: High doses of ketoconazole or itraconazole (greater than 200 mg/day) are not recommended.

Elbasvir/grazoprevir Glecaprevir/pibrentasvir Tenofovir disoproxil fumarate Not recommended during and 2 weeks after itraconazole treatment.

For administration instructions of other drugs whose absorption is dependent on gastric pH, refer to their prescribing information (e.g., atazanavir, erlotinib, ketoconazole, itraconazole, nilotinib, ledipasvir/sofosbuvir, and rilpivirine).

Although many of the clinical drug interactions in Table 1 are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with itraconazole. Although many of the clinical drug interactions in Table 2 are based on information with a similar azole antifungal, ketoconazole, these interactions are expected to occur with itraconazole.

7.4 Drugs without Clinically Significant Interactions with PREVYMIS No clinically significant interactions were observed in adult clinical drug-drug interaction studies of letermovir and acyclovir, digoxin, mycophenolate mofetil, fluconazole, itraconazole, posaconazole, ethinyl estradiol, and levonorgestrel.

Antifungals: ketoconazole*, itraconazole, voriconazole isavuconazonium sulfate* ↑ ketoconazole ↑ itraconazole ↓ voriconazole ↑ isavuconazonium High doses of ketoconazole (>200 mg/day) or itraconazole (> 200 mg/day) are not recommended.

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 ).

ketoconazole, isavuconazonium sulfate, itraconazole ↑ ketoconazole ↑ isavuconazonium sulfate ↑ itraconazole Refer to the ketoconazole, isavuconazonium sulfate, and itraconazole prescribing information for further information.

Examples: Inhibitors of CYP3A4: Macrolide antibiotics (e.g., erythromycin), azole-antifungal agents (e.g., ketoconazole, itraconazole), anti-retroviral agents, selective serotonin re-uptake inhibitors (SSRIs), protease inhibitors (e.g., ritonavir), NS3/4A inhibitors.

Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact: Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.

Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact: Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.

Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact: Omeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.

Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole / itraconazole ) Clinical Impact: Pantoprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.

Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact: Pantoprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.

Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact: Pantoprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.

Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact: Pantoprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.

Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Impact: Pantoprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.

Entrectinib Pemigatinib Talazoparib Refer to the entrectinib, pemigatinib and talazoparib prescribing information for dosing instructions if concomitant use cannot be avoided.

Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole, itraconazole) Clinical Impact: Rabeprazole can reduce the absorption of other drugs due to its effect on reducing intragastric acidity.

Azole Antifungal Agents: fluconazole itraconazole ketoconazole *† posaconazole voriconazole ↑ rilpivirine ↓ ketoconazole Concomitant use of rilpivirine tablets with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes).

Azole Antifungal Agents: fluconazole itraconazole ketoconazole This interaction study has been performed with a dose higher than the recommended dose for EDURANT assessing the maximal effect on the coadministered drug.

Antifungals: ketoconazole itraconazole voriconazole ↑ ketoconazole ↑ itraconazole ↓ voriconazole High doses of ketoconazole or itraconazole (greater than 200 mg per day) are not recommended.

Antivirals Simeprevir Not recommended during and 2 weeks after TOLSURA treatment.

However, strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent.

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 .