Ketoconazole

Ketoconazole is predicted to increase abemaciclib AUC up to 16-fold, leading to increased toxicity. Concomitant use should be avoided.

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) ] .

7 DRUG INTERACTIONS • Do not use almotriptan tablets and ergotamine-containing or ergot-type medications within 24 hours of each other ( 4.5 , 7.1 ) • Do not use almotriptan tablets and other 5-HT 1 agonist (e.g., triptans) within 24 hours of each other ( 4.6 , 7.2 ) • SSRI or SNRI: life-threatening serotonin syndrome reported during combined use with triptans ( 5.5 , 7.3 ) • Ketoconazole: use single dose of almotriptan tablets 6.25 mg; maximum almotriptan tablets daily dose 12.5 mg ( 7.4 ) 7.1 Ergot-Containing Drugs These drugs have been reported to cause prolonged vasospastic reactions. 7.4 Ketoconazole and Other Potent CYP3A4 Inhibitors Co-administration of almotriptan and oral ketoconazole, a potent CYP3A4 inhibitor, resulted in an approximately 60% increase in exposure of almotriptan.

7 DRUG INTERACTIONS Do not use almotriptan malate and ergotamine-containing or ergot-type medications within 24 hours of each other ( 4.5 , 7.1 ) Do not use almotriptan malate and other 5-HT 1 agonists (e.g., triptans) within 24 hours of each other ( 4.6 , 7.2 ) SSRI or SNRI: life-threatening serotonin syndrome reported during combined use with triptans ( 5.5 , 7.3 ) Ketoconazole: use single dose of almotriptan malate 6.25 mg; maximum almotriptan malate daily dose 12.5 mg ( 7.4 ) 7.1 Ergot-Containing Drugs These drugs have been reported to cause prolonged vasospastic reactions. 7.4 Ketoconazole and Other Potent CYP3A4 Inhibitors Coadministration of almotriptan and oral ketoconazole, a potent CYP3A4 inhibitor, resulted in an approximately 60% increase in exposure of almotriptan.

(See PRECAUTIONS: DRUG INTERACTIONS .) Additionally, the following other drugs are contraindicated with ketoconazole tablets: methadone, disopyramide, dronedarone, ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine, methylergometrine, irinotecan, lurasidone, oral midazolam, alprazolam, triazolam, felodipine, nisoldipine, ranolazine, tolvaptan, eplerenone, lovastatin, simvastatin and colchicine. (See PRECAUTIONS: DRUG INTERACTIONS .) Enhanced Sedation Coadministration of ketoconazole tablets with oral midazolam, oral triazolam or alprazolam has resulted in elevated plasma concentrations of these drugs. Concomitant administration of ketoconazole tablets with oral triazolam, oral midazolam or alprazolam is contraindicated.

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

7 DRUG INTERACTIONS • Avanafil can potentiate the hypotensive effect of nitrates, alpha-blockers, antihypertensives, and alcohol ( 7.1 ) • CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, erythromycin) increase avanafil exposure ( 7.2 ) 7.1 Potential for Pharmacodynamic Interactions with Avanafil Nitrates Administration of avanafil to patients who are using any form of organic nitrate, is contraindicated. Strong CYP3A4 Inhibitors Ketoconazole (400 mg daily), a selective and strong inhibitor of CYP3A4, increased avanafil 50 mg single-dose systemic exposure (AUC) and maximum concentration (C max) equal to 13-fold and 3-fold, respectively, and prolonged the half-life of avanafil to approximately 9 hours.

Strong CYP3A4 inhibitor causing eight-fold increase in systemic budesonide exposure. Avoid use.

Ketoconazole increases cisapride plasma concentrations, potentially causing QT prolongation and life-threatening ventricular tachyarrhythmias including torsades de pointes.

Coadministration of ketoconazole with colchicine is contraindicated.

Strong CYP3A4 inhibitor causing significant increases in colchicine plasma levels.

Significantly increased saxagliptin exposure. Do not coadminister with dapagliflozin and saxagliptin.

Coadministration of ketoconazole with dihydroergotamine is contraindicated.

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

(See PRECAUTIONS: DRUG INTERACTIONS .) Additionally, the following other drugs are contraindicated with ketoconazole tablets: methadone, disopyramide, dronedarone, ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine, methylergometrine, irinotecan, lurasidone, oral midazolam, alprazolam, triazolam, felodipine, nisoldipine, ranolazine, tolvaptan, eplerenone, lovastatin, simvastatin and colchicine.

Ketoconazole: (see WARNINGS, CONTRAINDICATIONS ) Concomitant use of ketoconazole is contraindicated. Ketoconazole at 400 mg daily (the maximum approved prescription dose) co-administered with dofetilide (500 mcg BID) for 7 days has been shown to increase dofetilide C max by 53% in males and 97% in females, and AUC by 41% in males and 69% in females.

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) ] .

Strong CYP3A4 inhibitor resulted in 2.2-fold increase in tamsulosin Cmax and 2.8-fold increase in AUC. Tamsulosin 0.4 mg should not be used in combination with strong CYP3A4 inhibitors.

Coadministration of ketoconazole with eplerenone is contraindicated.

Coadministration of ketoconazole with ergometrine is contraindicated.

Coadministration of ketoconazole with ergotamine is contraindicated.

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

Strong CYP3A4 inhibitor that significantly increases everolimus Cmax, AUC, and half-life. Should not be coadministered.

Strong CYP3A4 inhibitor significantly increases everolimus Cmax, AUC, and half-life; co-administration 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.

(See PRECAUTIONS: DRUG INTERACTIONS .) Additionally, the following other drugs are contraindicated with ketoconazole tablets: methadone, disopyramide, dronedarone, ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine, methylergometrine, irinotecan, lurasidone, oral midazolam, alprazolam, triazolam, felodipine, nisoldipine, ranolazine, tolvaptan, eplerenone, lovastatin, simvastatin and colchicine.

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

Strong CYP3A4 inhibitor increases plasma fluticasone propionate exposure 1.9-fold and decreases plasma cortisol AUC by 45%, potentially causing systemic corticosteroid effects.

Strong CYP3A4 inhibitor increases fluticasone propionate exposure 1.9-fold and decreases cortisol. With salmeterol, increases AUC 16-fold causing beta-2 agonist side effects including QTc prolongation, palpitations, and tachycardia.

Coadministration of ketoconazole with irinotecan is contraindicated.

CYP3A4 and UGT1A1 inhibitor increases exposure to irinotecan and active metabolite SN-38. Do not administer unless no therapeutic alternatives.

More than 5-fold increase in isavuconazole exposure. Contraindicated coadministration of all potent CYP3A4 inhibitors.

7 DRUG INTERACTIONS Consult approved product labeling for drugs that are substrates of CYP3A4, P-gp, OCT2, and MATE prior to initiating RECORLEV ( 7.1 ) Sensitive CYP3A4 or CYP3A4 and P-gp Substrates : Concomitant use of RECORLEV with these substrates is contraindicated or not recommended ( 7.1 ) Atorvastatin : Use lowest atorvastatin dose possible and monitor for adverse reactions for dosages exceeding 20 mg daily ( 7.1 ) Metformin : Monitor glycemia, kidney function, and vitamin B12 and adjust metformin dosage as needed ( 7.1 ) Strong CYP3A4 Inhibitors or Inducers : Avoid use of these drugs 2 weeks before and during RECORLEV treatment ( 7.2 ) Gastric Acid Modulators : See Full Prescribing Information for recommendations regarding concomitant use with RECORLEV ( 7.2 ) 7.1 Effect of RECORLEV on Other Drugs Levoketoconazole is a strong CYP3A4 inhibitor, as well as an inhibitor of the drug transporters P-gp, OCT2, and MATE1 in vivo. In vitro, levoketoconazole inhibits CYP2B6 and CYP2C8. c Based on clinical drug interaction study with levoketoconazole.

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.

(See PRECAUTIONS: DRUG INTERACTIONS .) Additionally, the following other drugs are contraindicated with ketoconazole tablets: methadone, disopyramide, dronedarone, ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine, methylergometrine, irinotecan, lurasidone, oral midazolam, alprazolam, triazolam, felodipine, nisoldipine, ranolazine, tolvaptan, eplerenone, lovastatin, simvastatin and colchicine. (See PRECAUTIONS: DRUG INTERACTIONS .) Myopathy Coadministration of CYP3A4 metabolized HMG-CoA reductase inhibitors such as simvastatin, and lovastatin is contraindicated with ketoconazole tablets.

Ketoconazole increases lurasidone exposure and may result in serious adverse reactions.

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

Strong CYP3A4 inhibitor approximately doubles macitentan exposure. Avoid co-administration.

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

Should not be administered with mefloquine or within 15 weeks of last mefloquine dose due to risk of potentially fatal QTc interval prolongation. Increases mefloquine Cmax by 64% and AUC by 79%.

Coadministration of ketoconazole with methadone is contraindicated.

Coadministration of ketoconazole with methylergometrine is contraindicated.

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.

(See PRECAUTIONS: DRUG INTERACTIONS .) Additionally, the following other drugs are contraindicated with ketoconazole tablets: methadone, disopyramide, dronedarone, ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine, methylergometrine, irinotecan, lurasidone, oral midazolam, alprazolam, triazolam, felodipine, nisoldipine, ranolazine, tolvaptan, eplerenone, lovastatin, simvastatin and colchicine. (See PRECAUTIONS: DRUG INTERACTIONS .) Enhanced Sedation Coadministration of ketoconazole tablets with oral midazolam, oral triazolam or alprazolam has resulted in elevated plasma concentrations of these drugs. Concomitant administration of ketoconazole tablets with oral triazolam, oral midazolam or alprazolam is contraindicated.

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

(See PRECAUTIONS: DRUG INTERACTIONS .) Additionally, the following other drugs are contraindicated with ketoconazole tablets: methadone, disopyramide, dronedarone, ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine, methylergometrine, irinotecan, lurasidone, oral midazolam, alprazolam, triazolam, felodipine, nisoldipine, ranolazine, tolvaptan, eplerenone, lovastatin, simvastatin and colchicine.

Ketoconazole increases pimozide plasma concentrations, potentially causing QT prolongation and life-threatening ventricular tachyarrhythmias including torsades de pointes.

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

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

Ketoconazole increases quinidine plasma concentrations, potentially causing QT prolongation and life-threatening ventricular tachyarrhythmias including torsades de pointes.

( 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.

Combined P-gp and strong CYP3A inhibitor that increases rivaroxaban exposure and may increase bleeding risk. Avoid concomitant administration.

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 causing 3.8-fold increase in silodosin maximum plasma concentrations and 3.2-fold increase in exposure. 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.

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

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

Strong CYP3A4 inhibitor; increases tamsulosin Cmax by 2.2-fold and AUC by 2.8-fold. Contraindicated due to potential for significant exposure increase.

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

Coadministration of ketoconazole with tolvaptan is contraindicated.

(See PRECAUTIONS: DRUG INTERACTIONS .) Additionally, the following other drugs are contraindicated with ketoconazole tablets: methadone, disopyramide, dronedarone, ergot alkaloids such as dihydroergotamine, ergometrine, ergotamine, methylergometrine, irinotecan, lurasidone, oral midazolam, alprazolam, triazolam, felodipine, nisoldipine, ranolazine, tolvaptan, eplerenone, lovastatin, simvastatin and colchicine. (See PRECAUTIONS: DRUG INTERACTIONS .) Enhanced Sedation Coadministration of ketoconazole tablets with oral midazolam, oral triazolam or alprazolam has resulted in elevated plasma concentrations of these drugs. Concomitant administration of ketoconazole tablets with oral triazolam, oral midazolam or alprazolam is contraindicated.

Strong CYP3A4 inhibitor resulting in significant increase in ubrogepant exposure. Contraindicated for concomitant use.

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 )] . Strong CYP3A4 inhibitors Ketoconazole (200 mg once daily) produced a 10-fold increase in vardenafil area under the curve (AUC) and a 4-fold increase in maximum concentration (C max ) when co-administered with vardenafil 5 mg in healthy volunteers.

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

ketoconazole), and protease inhibitors(e.g., ritonavir), may result in an increase in codeine plasma concentrations , with subsequently greater metabolism by CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of acetaminophen and codeine phosphate tablets is achieved (see WARNINGS ).

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

Combined P-gp and strong CYP3A4 inhibitor that increases apixaban exposure and bleeding risk. Reduce apixaban dose by 50% or avoid coadministration.

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 )].

Antipsychotics, Anxiolytics and Hypnotics Lurasidone, alprazolam, oral midazolam, pimozide, triazolam aripiprazole, buspirone, haloperidol, midazolam IV, quetiapine, ramelteon, risperidone The increase in plasma concentrations of lurasidone when coadministered with ketoconazole tablets may increase the risk of serious side effects (See CONTRAINDICATIONS ). Aripiprazole: Coadministration of ketoconazole (200 mg/day for 14 days) with a 15 mg single dose of aripiprazole increased the AUC of aripiprazole and its active metabolite by 63% and 77%, respectively. When ketoconazole is given concomitantly with aripiprazole, them aripiprazole dose should be reduced to one-half of the recommended dose.

Strong CYP3A4/5 inhibitor increases axitinib plasma exposure. Co-administration should be avoided; if unavoidable, reduce axitinib dose.

Strong CYP3A4 inhibitor that increases fluticasone propionate plasma exposure and reduces cortisol AUC. Caution should be exercised when coadministered.

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

Decreases metabolism of betamethasone by up to 60%, leading to increased risk of corticosteroid side effects.

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

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

CYP3A4 inhibitor (azole-antifungal) that increases buprenorphine plasma concentration, resulting in increased or prolonged opioid effects.

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

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

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

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

( 2.2 , 7.2 ) 7.1 Effect of CYP3A4 Inhibitors Administration of a strong CYP3A4 inhibitor, ketoconazole to healthy subjects increased single-dose plasma cabozantinib exposure by 38%. 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 )] .

Potent CYP3A4 enzyme inducer that may decrease ketoconazole bioavailability and reduce antifungal efficacy. Coadministration not recommended.

Strong CYP3A4/P-gp inhibitor increased systemic exposure of ceritinib, which may increase incidence and severity of adverse reactions. Avoid concurrent use or reduce ZYKADIA dose if unavoidable.

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

ketoconazole), or protease inhibitors (e.g., ritonavir), may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of TUXARIN ER is achieved [ see Warnings and Precautions (5.8) ].

Azole antifungal CYP3A4 inhibitor that increases codeine and morphine levels, potentially causing fatal respiratory depression.

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

Eletriptan: Eletriptan should be used with caution with ketoconazole, and specifically, should not be used within at least 72 hours of treatment with ketoconazole Antineoplastics irinotecan dasatinib, lapatinib, nilotinib bortezomib, busulphan, docetaxel, erlotinib, imatinib, ixabepilone, paclitaxel, trimetrexate, vinca alkaloids Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with ketoconazole tablets may increase the risk of potentially fatal adverse events.

Ketoconazole significantly decreases corticosteroid metabolism by up to 60%, leading to increased risk of side effects.

Ketoconazole, a strong CYP 3A4 inhibitor, may decrease metabolism of corticosteroids by up to 60%, leading to increased plasma concentrations.

Inhibits hepatic enzymes (CYP3A and 2C19), leading to increased and prolonged sedation.

Potent CYP3A4 inhibitor may result in potentially fatal interaction with disopyramide.

Potent CYP3A4 inhibitor that increases docetaxel exposure 2.2-fold when coadministered. Concomitant use should be avoided; if unavoidable, dose reduction and close toxicity monitoring required.

Potent CYP3A4 inhibitor that increased docetaxel exposure 2.2-fold in vivo. Concomitant use should be avoided; if unavoidable, close monitoring for toxicity and dose reduction considered.

Potent CYP3A4 enzyme inducer that may decrease ketoconazole bioavailability and reduce antifungal efficacy. Coadministration not recommended.

Strong CYP3A inhibitor increases ivacaftor AUC 8.5-fold and significantly increases elexacaftor and tezacaftor exposures. TRIKAFTA dosage reduction required.

Eletriptan: Eletriptan should be used with caution with ketoconazole, and specifically, should not be used within at least 72 hours of treatment with ketoconazole Antineoplastics irinotecan dasatinib, lapatinib, nilotinib bortezomib, busulphan, docetaxel, erlotinib, imatinib, ixabepilone, paclitaxel, trimetrexate, vinca alkaloids Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with ketoconazole tablets may increase the risk of potentially fatal adverse events.

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).

Potent CYP3A4 inhibitor increases eszopiclone exposure and effects. Dose reduction of eszopiclone is needed.

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

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

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

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

Strong CYP3A4 inhibitor causing approximately doubling of fesoterodine active metabolite exposure. Doses greater than 4 mg not recommended in adults.

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)] .

CYP3A4 inhibitor that significantly increases guanfacine plasma concentrations and exposure. Dose reduction to 50% of target dosage recommended.

CYP3A4 inhibitor that significantly increases haloperidol concentrations; increased QTc prolongation observed when combined with paroxetine.

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

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

Azole-antifungal CYP3A4 inhibitor that can increase hydrocodone plasma concentration and opioid effects.

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

Azole-antifungal CYP3A4 inhibitor that increases hydrocodone plasma concentration, resulting in increased or prolonged opioid effects.

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

Ketoconazole decreases corticosteroid metabolism by up to 60%, increasing risk of corticosteroid side effects.

Ketoconazole significantly decreases metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.

Eletriptan: Eletriptan should be used with caution with ketoconazole, and specifically, should not be used within at least 72 hours of treatment with ketoconazole Antineoplastics irinotecan dasatinib, lapatinib, nilotinib bortezomib, busulphan, docetaxel, erlotinib, imatinib, ixabepilone, paclitaxel, trimetrexate, vinca alkaloids Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with ketoconazole tablets may increase the risk of potentially fatal adverse events.

Ketoconazole AUC is decreased by up to 88% when combined with isoniazid and rifampin after 5 months of concurrent therapy.

Strong CYP3A4 inhibitor increases istradefylline AUC by 2.5-fold. Recommended maximum dosage is 20 mg once daily.

Strong CYP3A inhibitor significantly increased ivacaftor exposure 8.5-fold. Dosage reduction recommended for patients ≥6 months; not recommended for patients <6 months.

Decreases metabolism of triamcinolone acetonide by up to 60%, increasing risk of corticosteroid side effects.

Eletriptan: Eletriptan should be used with caution with ketoconazole, and specifically, should not be used within at least 72 hours of treatment with ketoconazole Antineoplastics irinotecan dasatinib, lapatinib, nilotinib bortezomib, busulphan, docetaxel, erlotinib, imatinib, ixabepilone, paclitaxel, trimetrexate, vinca alkaloids Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with ketoconazole tablets may increase the risk of potentially fatal adverse events.

Ketoconazole decreases the metabolism of corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects.

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

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

Drug Interactions because of this product's effect on gastrointestinal motility and gastric emptying, it may decrease the absorption of other oral medications during concurrent use such as: urinary alkalizers; thiazide diuretics (may cause the urine to become alkaline reducing the effectiveness of methenamine by inhibiting its conversion to formaldehyde); antimuscarinics (concurrent use may intensify antimuscarinic effects of hyoscyamine because of secondary antimuscarinic activities of these medications); antacids/antidiarrheals (may reduce absorption of hyoscyamine, concurrent use with antacids may cause urine to become alkaline reducing effectiveness of methenamine by inhibiting its conversion to formaldehyde) doses of these medications should be spaced 1 hour apart from doses of hyoscyamine; antimyasthenics (concurrent use with hyoscyamine may further reduce intestinal motility); ketoconazole (patients should be advised to take this combination at least 2 hours after ketoconazole); monoamine oxidase (MAO) Inhibitors (concurrent use may intensify antimuscarinic side effects, opoid (narcotic) analgesics may result in increased risk of severe constipation); sulfonamides (these drugs may precipitate with formaldehyde in the urine, increasing the danger of crystalluria).

Significantly decreases corticosteroid metabolism by up to 60%, leading to increased risk of corticosteroid side effects.

Ketoconazole significantly decreases corticosteroid metabolism by up to 60%, leading to increased risk of side effects.

Ketoconazole significantly decreases corticosteroid metabolism by up to 60%, leading to increased risk of side effects.

Significantly decreases corticosteroid metabolism by up to 60%, leading to increased risk of corticosteroid side effects.

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

Potent CYP3A4 enzyme inducer that may decrease ketoconazole bioavailability and reduce antifungal efficacy. Coadministration not recommended.

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

Eletriptan: Eletriptan should be used with caution with ketoconazole, and specifically, should not be used within at least 72 hours of treatment with ketoconazole Antineoplastics irinotecan dasatinib, lapatinib, nilotinib bortezomib, busulphan, docetaxel, erlotinib, imatinib, ixabepilone, paclitaxel, trimetrexate, vinca alkaloids Irinotecan: The potential increase in plasma concentrations of irinotecan when coadministered with ketoconazole tablets 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.

Ketoconazole increases systemic exposure of ospemifene by 1.4-fold, increasing risk of adverse reactions when used chronically.

Mean oxybutynin chloride plasma concentrations were approximately 3 to 4 fold higher when co-administered with ketoconazole, a potent CYP3A4 inhibitor.

The label of the coadministered drug should be consulted for information on dose adjustment and adverse effects 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 ketoconazole tablets may increase the risk of serious cardiovascular events including QT prolongation and torsade de pointes, or respiratory or CNS depression [See CONTRAINDICATIONS .] Fentanyl: The potential increase in plasma concentrations of fentanyl when coadministered with ketoconazole tablets may increase the risk of potentially fatal respiratory depression.

Azole-antifungal CYP3A4 inhibitor that increases plasma concentration of oxycodone, resulting in increased or prolonged opioid effects.

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

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

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

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.

Potent CYP3A4 enzyme inducer that may decrease ketoconazole bioavailability and reduce antifungal efficacy. Coadministration not recommended.

Ketoconazole decreases metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects.

ketoconazole), or protease inhibitors (e.g., ritonavir), may result in an increase in codeine plasma concentrations with subsequently greater metabolism by cytochrome CYP2D6, resulting in greater morphine levels, which could increase or prolong adverse reactions and may cause potentially fatal respiratory depression, particularly when an inhibitor is added after a stable dose of Promethazine and Phenylephrine HCl and Codeine Phosphate Oral Solution is achieved [see Warnings and Precautions (5.9) ] .

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

Strong CYP3A4 inhibitor significantly increases quetiapine exposure; reduce quetiapine dose to one sixth of original dose.

Strong CYP3A4 inhibitor that significantly increases quetiapine exposure; quetiapine dose should be reduced to one sixth of original dose.

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

Potent CYP3A4 enzyme inducer that may decrease ketoconazole bioavailability and reduce antifungal efficacy. Coadministration not recommended.

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.

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

Strong CYP3A4 inhibitor increases salmeterol AUC 16-fold and Cmax 1.4-fold, associated with QTc prolongation, palpitations, and tachycardia in clinical trials.

Coadministration significantly increases saxagliptin plasma concentrations. Saxagliptin dosage should be limited to 2.5 mg once daily.

Strong CYP3A4/5 inhibitor that significantly increases saxagliptin concentrations. Dose limitation to 2.5 mg/1,000 mg once daily required.

Concomitant use significantly increased solifenacin exposure. Dosage of solifenacin greater than 5 mg once daily is not recommended.

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

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

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). Ketoconazole: In a study of 6 normal volunteers, a significant increase in tacrolimus oral bioavailability (14 ± 5% vs. 30 ± 8%) was observed with concomitant ketoconazole administration (200 mg).

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).

Potent CYP3A4 inhibitor increases tolterodine Cmax and AUC 2- to 2.5-fold in poor metabolizers. Dose reduction to 2 mg once daily recommended.

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

Strong CYP3A4 inhibitor that increases toremifene Cmax 1.4-fold and AUC 2.9-fold; should be avoided.

7 DRUG INTERACTIONS CYP3A inhibitors: Avoid concomitant strong CYP3A inhibitors ( 7.1 ) CYP3A inducers: Avoid concomitant strong CYP3A inducers ( 7.2 ) 7.1 Effect of Cytochrome CYP3A Inhibitors Coadministration of YONDELIS with ketoconazole, a strong CYP3A inhibitor, increased systemic exposure of trabectedin by 66%. 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. Drug Interactions Effect of Strong CYP3A Inhibitors on Trabectedin Coadministration of multiple doses of ketoconazole (200 mg twice daily for 7.5 days) with a single dose of YONDELIS (0.58 mg/m 2 ) on day 1 increased trabectedin dose-normalized AUC by 66% and C max by 22% compared to a single YONDELIS dose (1.3 mg/m 2 ) given alone.

ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of tramadol hydrochloride tablets and CYP3A4 inducers can decrease the plasma concentration of tramadol[see Clinical Pharmacology (12.3)], resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol.After stopping a CYP3A4 inducer, as the effects of the inducer decline, the tramadol plasma concentration will increase[see Clinical Pharmacology (12.3)], which could increase or prolong both the therapeutic effects and adverse reactions, and may cause seizures, serotonin syndrome, and/or potentially fatal respiratory depression.

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

Strong CYP3A4 inhibitor increases tretinoin plasma concentration, which may increase the risk of adverse reactions.

Ketoconazole decreases metabolism of corticosteroids by up to 60%, leading to increased risk of adverse effects.

Drug Interactions because of this product's effect on gastrointestinal motility and gastric emptying, it may decrease the absorption of other oral medications during concurrent use such as: urinary alkalizers; thiazide diuretics (may cause the urine to become alkaline reducing the effectiveness of methenamine by inhibiting its conversion to formaldehyde); antimuscarinics (concurrent use may intensify antimuscarinic effects of hyoscyamine because of secondary antimuscarinic activities of these medications); antacids/antidiarrheals (may reduce absorption of hyoscyamine, concurrent use with antacids may cause urine to become alkaline reducing effectiveness of methenamine by inhibiting its conversion to formaldehyde) doses of these medications should be spaced 1 hour apart from doses of hyoscyamine; antimyasthenics (concurrent use with hyoscyamine may further reduce intestinal motility); ketoconazole (patients should be advised to take this combination at least 2 hours after ketoconazole); monoamine oxidase (MAO) Inhibitors (concurrent use may intensify antimuscarinic side effects, opioid (narcotic) analgesics may result in increased risk of severe constipation); sulfonamides (these drugs may precipitate with formaldehyde in the urine, increasing the danger of crystalluria).

Strong CYP3A4 inhibitor producing a 10-fold increase in vardenafil AUC and 4-fold increase in Cmax, significantly increasing vardenafil exposure and risk of adverse effects.

Potent CYP3A4 inhibitor that increases zolpidem exposure and pharmacodynamic effects. Lower dose of zolpidem should be considered.

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

After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased. 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) ] .

Ketoconazole, a strong CYP3A4 inhibitor, increases alosetron AUC by 29%. Use with caution due to increased alosetron exposure.

Ketoconazole, a strong CYP3A4 inhibitor, increased alosetron AUC by 29%. Caution should be used when administered concomitantly.

Reduces gastric acidity and impairs ketoconazole absorption from tablets. Should be administered at least 1 hour before or 2 hours after ketoconazole.

Strong CYP3A4 inhibitor may increase plasma concentrations of amlodipine to a greater extent. Monitor for symptoms of hypotension and edema.

Imidazoles may induce fungal resistance to amphotericin B. Combination therapy should be administered with caution, especially in immunocompromised patients.

In vitro and in vivo animal studies suggest imidazoles may induce fungal resistance to amphotericin B. Combination therapy should be administered with caution, especially in immunocompromised patients.

Reduce gastric acidity and impair ketoconazole absorption from tablets. Ketoconazole should be taken with acidic beverage during coadministration.

7.2 Ketoconazole Concurrent oral administration of ketoconazole, a potent CYP3A4 inhibitor, with a single dose of Coartem Tablets resulted in a moderate increase in exposure to artemether, DHA, and lumefantrine in a study of 15 healthy subjects. No dose adjustment of Coartem Tablets is necessary when administered with ketoconazole or other potent CYP3A4 inhibitors.

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

Co-administration with ketoconazole, a potent CYP3A4 inhibitor, increases exposure to MMAE, which may increase the risk of adverse reactions. Closely monitor adverse reactions.

After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased. 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) ] .

After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased. 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 increases buprenorphine plasma concentration, resulting in increased or prolonged opioid effects including respiratory depression and sedation.

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

Decreases caffeine elimination; lower caffeine doses may be needed when coadministered.

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.

May inhibit synthetic and catabolic enzymes of calcitriol, reducing serum endogenous calcitriol concentrations.

Ketoconazole may inhibit synthetic and catabolic enzymes of calcitriol, potentially reducing serum calcitriol concentrations.

Co-administration of ciclesonide with ketoconazole, a potent CYP3A4 inhibitor, increased exposure (AUC) of des-ciclesonide approximately 3.6-fold at steady state.

Cimetidine may alter gastric pH and affect ketoconazole absorption. Ketoconazole should be given at least 2 hours before cimetidine administration.

Cimetidine-induced pH alteration may affect ketoconazole absorption. Ketoconazole should be given at least 2 hours before cimetidine.

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.

Potent CYP3A4 inhibitor that might decrease clearance of citalopram, though clinical study showed no significant pharmacokinetic effect.

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

Increases cyclosporine concentrations via CYP3A4 inhibition. Also may potentiate renal dysfunction. Dosage adjustment essential.

In patients with moderate renal impairment (CrCl 30 to 50 mL/min), reduce the dosage of dabigatran etexilate to 75 mg twice daily when administered concomitantly with the P-gp inhibitors dronedarone or systemic ketoconazole. 7.3 Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism in Adult Patients Following Hip Replacement Surgery In patients with CrCl ≥50 mL/min who have concomitant administration of P-gp inhibitors such as dronedarone or systemic ketoconazole, it may be helpful to separate the timing of administration of dabigatran and the P-gp inhibitor by several hours.

In patients with moderate renal impairment (CrCl 30-50 mL/min), reduce the dosage of PRADAXA to 75 mg twice daily when administered concomitantly with the P-gp inhibitors dronedarone or systemic ketoconazole. 7.3 Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism in Adult Patients Following Hip Replacement Surgery In patients with CrCl ≥ 50 mL/min who have concomitant administration of P-gp inhibitors such as dronedarone or systemic ketoconazole, it may be helpful to separate the timing of administration of PRADAXA and the P-gp inhibitor by several hours.

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.

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

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

Drugs which inhibit CYP 3A4 (e.g., ketoconazole, macrolide antibiotics such as erythromycin) have the potential to result in increased plasma concentrations of corticosteroids. Ketoconazole: Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects. In addition, ketoconazole alone can inhibit adrenal corticosteroid synthesis and may cause adrenal insufficiency during corticosteroid withdrawal.

Ketoconazole, a strong CYP3A4 inhibitor, has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects. In addition, ketoconazole alone can inhibit adrenal corticosteroid synthesis and may cause adrenal insufficiency during corticosteroid withdrawal.

CYP3A4 inhibitor causes 15% reduction in ropivacaine plasma clearance.

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

Increases digoxin concentrations; magnitude unclear. Requires monitoring and dose adjustment.

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) ] .

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

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

Substances increasing the systemic concentrations of hormonal contraceptives (HCs): In a clinical drug-drug interaction study conducted in premenopausal females, once daily co-administration of drospirenone (DRSP) 3 mg/ethinyl estradiol (EE) 0.02 mg containing tablets with strong CYP3A4 inhibitor, ketoconazole 200 mg twice daily for 10 days, resulted in a moderate increase of DRSP systemic exposure.

In a clinical drug-drug interaction study conducted in premenopausal women, once daily co-administration of DRSP 3 mg/E2 1.5 mg containing tablets with strong CYP3A4 inhibitor, ketoconazole 200 mg twice daily for 10 days resulted in a moderate increase of exposure and a mild increase of peak concentration for DRSP. The E2 exposure and peak concentration were unaffected by ketoconazole, although the exposure and peak concentration of estrone (E1) increased. 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. In a clinical drug-drug interaction study conducted in premenopausal women, once daily co-administration of DRSP 3 mg/EE 0.02 mg containing tablets with strong CYP3A4 inhibitor, ketoconazole 200 mg twice daily for 10 days resulted in a moderate increase of DRSP systemic exposure. In a clinical drug-drug interaction study conducted in 20 premenopausal women, co-administration of a DRSP (3 mg)/EE (0.02 mg) COC with the strong CYP3A4 inhibitor ketoconazole (200 mg twice daily) for 10 days increased the AUC(0-24h) of DRSP and EE by 2.68-fold (90% CI: 2.44, 2.95) and 1.40-fold (90% CI: 1.31, 1.49), respectively.

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. In a clinical drug-drug interaction study conducted in premenopausal women, once daily co-administration of DRSP 3 mg/EE 0.02 mg containing tablets with strong CYP3A4 inhibitor, ketoconazole 200 mg twice daily for 10 days resulted in a moderate increase of DRSP systemic exposure.

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. In a clinical drug-drug interaction study conducted in premenopausal women, once daily co-administration of DRSP 3 mg/EE 0.02 mg containing tablets with strong CYP3A4 inhibitor, ketoconazole 200 mg twice daily for 10 days resulted in a moderate increase of DRSP systemic exposure.

Esomeprazole can reduce ketoconazole absorption due to effects on gastric acid secretion.

Esomeprazole magnesium may interfere with ketoconazole bioavailability due to effects on gastric pH.

Esomeprazole magnesium may interfere with ketoconazole bioavailability due to effects on gastric pH.

Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, atazanavir, iron salts, erlotinib, and mycophenolate mofetil (MMF) can decrease, while the absorption of drugs such as digoxin can increase during treatment with omeprazole. Antiretroviral Drugs: Use with atazanavir and nelfinavir is not recommended; if saquinavir is used with esomeprazole strontium, monitor for toxicity and consider saquinavir dose reduction (7.1) May interfere with drugs for which gastric pH affects bioavailability (e.g., ketoconazole, iron salts, erlotinib, digoxin, and mycophenolate mofetil).

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

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

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

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

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

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

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

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

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

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

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

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.

7 DRUG INTERACTIONS Systemic Ketoconazole: Monitor during concomitant use. 7.2 Ketoconazole The blood levels of fingolimod and fingolimod-phosphate are increased by 1.7-fold when used concomitantly with ketoconazole. Patients who use fingolimod and systemic ketoconazole concomitantly should be closely monitored, as the risk of adverse reactions is greater.

7 DRUG INTERACTIONS • Systemic Ketoconazole: Monitor during concomitant use. 7.2 Ketoconazole The blood levels of fingolimod and fingolimod-phosphate are increased by 1.7-fold when used concomitantly with ketoconazole. Patients who use fingolimod and systemic ketoconazole concomitantly should be closely monitored, as the risk of adverse reactions is increased.

7 DRUG INTERACTIONS Systemic Ketoconazole : Monitor during concomitant use. 7.2 Ketoconazole The blood levels of fingolimod and fingolimod-phosphate are increased by 1.7-fold when used concomitantly with ketoconazole. Patients who use TASCENSO ODT and systemic ketoconazole concomitantly should be closely monitored, as the risk of adverse reactions is greater.

7 DRUG INTERACTIONS Strong cytochrome P450 3A4 inhibitors (e.g., ketoconazole): Use with caution. Concomitant administration of the strong CYP3A4 inhibitor ketoconazole increases the systemic exposure to fluticasone furoate. Caution should be exercised when considering the coadministration of Fluticasone Furoate ELLIPTA with ketoconazole and other known strong CYP3A4 inhibitors [see Warnings and Precautions ( 5.6 ), Clinical Pharmacology ( 12.3 )] .

7 DRUG INTERACTIONS • Strong cytochrome P450 3A4 inhibitors (e.g., ketoconazole): Use with caution. Concomitant administration of the strong CYP3A4 inhibitor ketoconazole increases the systemic exposure to fluticasone furoate and vilanterol. Caution should be exercised when considering the coadministration of Fluticasone Furoate/Vilanterol ELLIPTA with ketoconazole and other known strong CYP3A4 inhibitors [see Warnings and Precautions ( 5.9 ), Clinical Pharmacology ( 12.3 )] .

7 DRUG INTERACTIONS • Strong cytochrome P450 3A4 inhibitors (e.g., ketoconazole): Use with caution. Concomitant administration of the strong CYP3A4 inhibitor ketoconazole increases the systemic exposure to fluticasone furoate and vilanterol. Caution should be exercised when considering the coadministration of TRELEGY ELLIPTA with ketoconazole and other known strong CYP3A4 inhibitors [see Warnings and Precautions ( 5.9 ), Clinical Pharmacology ( 12.3 )] .

After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally administered budesonide increased. 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) ] .

Potent CYP3A4 inhibitor (when ritonavir-boosted) that may increase ketoconazole bioavailability. Should be used with caution and patients monitored closely.

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

Strong CYP3A4 inhibitor decreases gefitinib metabolism and increases plasma concentrations. Monitor for adverse reactions during concomitant use.

Table 14: Clinically Important Drug Interactions: Effect of other Drugs on Guanfacine Concomitant Drug Name or Drug Class Clinical Rationale and Magnitude of Drug Interaction Clinical Recommendation Strong and moderate CYP3A4 inhibitors, e.g., ketoconazole, fluconazole Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in an increase in exposure Consider dose reduction [see Dosage and administration (2.7)] Strong and moderate CYP3A4 inducers, e.g., rifampin, efavirenz Guanfacine is primarily metabolized by CYP3A4 and its plasma concentrations can be significantly affected resulting in a decrease in exposure Consider dose increase [see Dosage and administration (2.7)]

CYP3A4 inhibitor that increases haloperidol plasma concentrations; QTc prolongation observed when combined with paroxetine.

Inhibits metabolism of corticosteroids and decreases their clearance, requiring dose titration to avoid steroid toxicity.

Absorption of ketoconazole may be decreased during concurrent use due to decreased gastrointestinal motility and delayed gastric emptying.

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

Strong CYP3A4 inhibitor that increased iloperidone AUC by 57%, metabolite P88 by 55%, and P95 by 35%. Dose reduction required.

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

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

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

CYP3A4 inhibitor ketoconazole may increase plasma hormone levels.

CYP3A4 inhibitor that may increase plasma hormone levels.

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

Reduce gastric acidity and impair ketoconazole absorption from tablets. Ketoconazole should be taken with acidic beverage during coadministration.

Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects.

Ketoconazole inhibits CYP3A4, which may increase donepezil levels in vitro; clinical significance unknown.

May cause increased gastrointestinal pH resulting in marked reduction in ketoconazole absorption. Take combination at least 2 hours after ketoconazole.

Hepatic Enzyme Inhibitors (e.g., ketoconazole, macrolide antibiotics such as erythromycin and troleandomycin): Drugs which inhibit cytochrome P450 3A4 have the potential to result in increased plasma concentrations of corticosteroids. Ketoconazole : Ketoconazole has been reported to significantly decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects.

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).

Drug interaction study conducted; no dose adjustment recommended when coadministered with mirabegron.

Ketoconazole increases mirtazapine peak plasma levels by approximately 40% and AUC by 50%. Caution should be exercised when coadministering.

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) ] .

After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally inhaled mometasone furoate increased. 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) ] .

After oral administration of ketoconazole, a strong inhibitor of CYP3A4, the mean plasma concentration of orally inhaled mometasone furoate increased. 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) ] .

P-gp and CYP3A4 inhibitor that increased nintedanib exposure by 60%. Monitor patients closely for tolerability.

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.

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

Strong dual CYP and P-gp inhibitor increases maximum plasma concentrations and AUC of olodaterol 1.7-fold.

Monitor for toxicity and consider dose reduction of saquinavir ( 7.1 ) • May interfere with drugs for which gastric pH affects bioavailability (e.g., ketoconazole, iron salts, erlotinib, ampicillin esters, and digoxin). Like with other drugs that decrease the intragastric acidity, the absorption of drugs such as ketoconazole, ampicillin esters, iron salts and erlotinib can decrease, while the absorption of drugs such as digoxin can increase during treatment with omeprazole.

Omeprazole and sodium bicarbonate may reduce absorption of ketoconazole by decreasing gastric pH.

Strong CYP3A4 inhibitor increases systemic exposure of oxybutynin approximately 2-fold. Caution should be used when co-administered.

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

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.

Pantoprazole sodium can reduce absorption of ketoconazole due to its effect on reducing intragastric acidity.

Pantoprazole can reduce ketoconazole absorption by decreasing intragastric acidity, where gastric pH is important for bioavailability.

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

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

Cytochrome P450 3A4 inhibitor that may increase pravastatin bioavailability.

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.

Drugs which inhibit CYP 3A4 (e.g., ketoconazole, itraconazole, ritonavir, indinavir, macrolide antibiotics such as erythromycin ) have the potential to result in increased plasma concentrations of corticosteroids. Ketoconazole Ketoconazole has been reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to increased risk of corticosteroid side effects. In addition, ketoconazole alone can inhibit adrenal corticosteroid synthesis and may cause adrenal insufficiency during corticosteroid withdrawal.

Ketoconazole increases quinidine levels through competition for P450 IIIA4 metabolic pathway.

Quinidine levels rise due to competition for the P450 IIIA4 metabolic pathway.

CYP3A4 inhibitor. No change in quinine dosage necessary but patients should be monitored closely for adverse reactions associated with quinine.

CYP3A4 inhibitor. No change in quinine dosage necessary, but patients should be monitored closely for adverse reactions associated with quinine.

Approximately 30% decrease in ketoconazole bioavailability due to increased gastric pH. Patients may need monitoring.

( 7.1 ) Ketoconazole (strong CYP3A4 inhibitor): Increases AUC for ramelteon; administer with caution. Ketoconazole (strong CYP3A4 inhibitor) The AUC 0-inf and C max of ramelteon increased by approximately 84% and 36% upon coadministration of ketoconazole with ramelteon. Ramelteon should be administered with caution in subjects taking strong CYP3A4 inhibitors such as ketoconazole [see Clinical Pharmacology (12.5) ] .

Oral ketoconazole exposure reduced up to 95% when coadministered with ranitidine regimen maintaining gastric pH above 6. Effect at usual doses unknown.

Oral ketoconazole exposure reduced by up to 95% when coadministered with ranitidine regimens maintaining gastric pH above 6. Degree of interaction at usual doses is unknown.

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.

Potent CYP3A4 inhibitor that may increase ketoconazole bioavailability. Should be used with caution and patients monitored for signs of increased pharmacologic effects.

CYP3A4 inhibitor caused 15% reduction in plasma clearance of ropivacaine.

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

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

Sucralfate reduces the bioavailability of ketoconazole. Monitor absorption when used concomitantly.

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 increases sirolimus (primary metabolite) AUC 3.1-fold and Cmax 2.2-fold. Dose adjustment of temsirolimus recommended if alternative cannot be used.

Potent CYP3A4 inhibitor increased sirolimus (primary metabolite) AUC 3.1-fold and Cmax 2.2-fold. Dose adjustment of temsirolimus recommended if alternative cannot be used.

Ketoconazole is an inhibitor of CYP2C9 and CYP3A4 likely to substantially increase systemic exposure of terbinafine when concomitantly administered.

As a CYP2C9 and CYP3A4 inhibitor, likely to substantially increase terbinafine systemic exposure similar to fluconazole.

As a CYP2C9 and CYP3A4 inhibitor, ketoconazole may substantially increase systemic exposure of terbinafine (Cmax and AUC).

7 DRUG INTERACTIONS Potential for other drugs to affect tezacaftor/ivacaftor CYP3A inhibitors: Reduce SYMDEKO dosage when co-administered with strong (e.g., ketoconazole) or moderate (e.g., fluconazole) CYP3A inhibitors. Examples of strong CYP3A inhibitors include: ketoconazole, itraconazole, posaconazole, and voriconazole telithromycin and clarithromycin Co-administration of fluconazole increased ivacaftor exposure (AUC) by 3.0-fold.

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.

Table 7: Clinically Significant Interactions Affecting XELJANZ/XELJANZ XR When Concomitantly Used with Other Drugs Strong CYP3A4 Inhibitors (e.g., ketoconazole) Clinical Impact Increased exposure to tofacitinib Intervention Dosage modification of XELJANZ/XELJANZ XR is recommended [see Dosage and Administration (2) , Clinical Pharmacology, Figure 3 (12.3) ] Moderate CYP3A4 Inhibitors Concomitantly Used with Strong CYP2C19 Inhibitors (e.g., fluconazole) Clinical Impact Increased exposure to tofacitinib Intervention Dosage modification of XELJANZ/XELJANZ XR is recommended [see Dosage and Administration (2) , Clinical Pharmacology, Figure 3 (12.3) ] Strong CYP3A4 Inducers (e.g., rifampin) Clinical Impact Decreased exposure to tofacitinib and may result in loss of or reduced clinical response Intervention Concomitant use with XELJANZ/XELJANZ XR is not recommended [see Clinical Pharmacology, Figure 3 (12.3) ] Immunosuppressive Drugs (e.g., azathioprine, tacrolimus, cyclosporine) Clinical Impact Risk of added immunosuppression; concomitant use of XELJANZ/XELJANZ XR with biologic DMARDs or potent immunosuppressants has not been studied in patients with RA, PsA, AS, UC, or pcJIA.

CYP 3A4 inhibitors (e.g., ketoconazole) Ketoconazole, a strong CYP3A4 inhibitor, has been reported to decrease the metabolism of certain corticosteroids by up to 60% leading to an increased risk of corticosteroid side effects.

CYP3A4 inhibitor increases plasma concentrations of ulipristal acetate.

7 DRUG INTERACTIONS • Strong cytochrome P450 3A4 inhibitors (e.g., ketoconazole): Use with caution. Concomitant administration of the strong CYP3A4 inhibitor ketoconazole increases the systemic exposure to vilanterol. Caution should be exercised when considering the coadministration of ANORO ELLIPTA with ketoconazole and other known strong CYP3A4 inhibitors [see Warnings and Precautions ( 5.4 ), Clinical Pharmacology ( 12.3 )] .

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

CYP2D6 and CYP3A4 inhibitor that increases venlafaxine and O-desmethylvenlafaxine AUC and Cmax. Caution advised.

Increases venlafaxine and O-desmethylvenlafaxine AUC and Cmax. Caution when using venlafaxine with substances that inhibit both CYP2D6 and CYP3A4.

Increases venlafaxine and O-desmethylvenlafaxine AUC and Cmax. Caution when using venlafaxine with CYP2D6 and CYP3A4 inhibitors.

Ketoconazole, a potent CYP3A4 inhibitor, increases ziprasidone AUC and Cmax by approximately 35-40%.

Ketoconazole, a potent CYP3A4 inhibitor, increases ziprasidone AUC and Cmax by approximately 35-40%.

Ketoconazole, a potent CYP3A4 inhibitor, increases ziprasidone AUC and Cmax by approximately 35-40%.

Potent CYP3A4 inhibitor that increased pharmacodynamic effects of zolpidem; lower dose consideration recommended.

Strong CYP3A4 inhibitor had no clinically meaningful effect on abiraterone pharmacokinetics.

Strong CYP3A4 inhibitor had no clinically meaningful effect on abiraterone pharmacokinetics.

No clinically significant interaction found.

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

No clinically meaningful differences in eribulin mesylate exposure observed when administered with ketoconazole, a strong CYP3A4 and P-gp inhibitor.

Potent CYP 3A4 inhibitor with no significant effect on exemestane pharmacokinetics in clinical study.

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

Conversion of losartan to its active metabolite after intravenous administration is not affected by ketoconazole.

Ketoconazole did not affect conversion of losartan to active metabolite after intravenous administration. No clinically significant interaction.

Selective CYP3A4/3A5 inhibitor decreased Cmax by 34-46% but did not affect platelet aggregation inhibition or AUC/Tmax.

albuterol, systemic and inhaled amoxicillin ampicillin, with or without sulbactam atenolol azithromycin caffeine, dietary ingestion cefaclor co-trimoxazole (trimethoprim and sulfamethoxazole) diltiazem dirithromycin enflurane famotidine felodipine finasteride hydrocortisone isoflurane isoniazid isradipine influenza vaccine ketoconazole lomefloxacin mebendazole medroxyprogesterone methylprednisolone metronidazole metoprolol nadolol nifedipine nizatidine norfloxacin ofloxacin omeprazole prednisone, prednisolone ranitidine rifabutin roxithromycin sorbitol (purgative doses do not inhibit theophylline absorption) sucralfate terbutaline, systemic terfenadine tetracycline tocainide The Effect of Other Drugs on Theophylline Serum Concentration Measurements: Most serum theophylline assays in clinical use are immunoassays which are specific for theophylline.

Examples: Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole.

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

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.

Examples: Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole.

Lipid Regulating Drugs lovastatin, simvastatin atorvastatin The potential increase in plasma concentrations of atorvastatin, lovastatin and simvastatin when coadministered with ketoconazole tablets may increase the risk of skeletal Muscle toxicity, including rhabdomyolysis.

Examples: Erythromycin, clarithromycin, itraconazole, ketoconazole, posaconazole, and voriconazole.

Other Inhibitors and Inducers of CYP3A4 Substances that inhibit CYP3A4, such as ketoconazole or ritonavir, may inhibit buspirone metabolism and increase plasma concentrations of buspirone while substances that induce CYP3A4, such as dexamethasone or certain anticonvulsants (phenytoin, phenobarbital, carbamazepine), may increase the rate of buspirone metabolism.

Other inhibitors and inducers of CYP3A4: Substances that inhibit CYP3A4, such as ketoconazole or ritonavir, may inhibit buspirone metabolism and increase plasma concentrations of buspirone while substances that induce CYP3A4, such as dexamethasone or certain anticonvulsants (phenytoin, phenobarbital, carbamazepine), may increase the rate of buspirone metabolism.

Ketoconazole Combined administration of citalopram (40 mg) and ketoconazole (200 mg) decreased the C max and AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram.

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

No clinically significant changes in concentration were observed for doravirine when co-administered with the following agents: dolutegravir, TDF, lamivudine, elbasvir and grazoprevir, ledipasvir and sofosbuvir, ritonavir, ketoconazole, aluminum hydroxide/magnesium hydroxide/simethicone containing antacid, pantoprazole, and methadone [see Clinical Pharmacology (12.3) ].

No clinically significant changes in concentration were observed for doravirine when co-administered with the following agents: TDF, lamivudine, elbasvir and grazoprevir, ledipasvir and sofosbuvir, ritonavir, ketoconazole, aluminum hydroxide/magnesium hydroxide/simethicone containing antacid, pantoprazole, or methadone [see Clinical Pharmacology (12.3) ] .

ketoconazole ↓ ketoconazole Drug interaction trials with efavirenz, emtricitabine and tenofovir disoproxil fumarate and ketoconazole have not been conducted. Efavirenz has the potential to decrease plasma concentrations of ketoconazole.

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

Antifungals: oral Ketoconazole These interactions have been studied in healthy adults. ↑ EBR ↑ GZR Co-administration of oral ketoconazole is not recommended.

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. ↓ ketoconazole , No dose adjustment is required when COMPLERA is coadministered with azole antifungal agents.

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. ↑­ TAF ↓ ketoconazole , No dosage adjustment is required when ODEFSEY is coadministered with azole antifungal agents.

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. ↓ ketoconazole , No dose adjustment is required when emtricitabine, rilpivirine and tenofovir disoproxil fumarate tablets are coadministered with azole antifungal agents.

7.16 Ketoconazole Combined administration of racemic citalopram (40 mg) and ketoconazole (200 mg), a potent CYP3A4 inhibitor, decreased the C max and AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram.

7.16 Ketoconazole Combined administration of racemic citalopram (40 mg) and ketoconazole (200 mg), a potent CYP3A4 inhibitor, decreased the C max and AUC of ketoconazole by 21% and 10%, respectively, and did not significantly affect the pharmacokinetics of citalopram.

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.

Additionally, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam.

Additionally, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam.

The metabolism of fluvoxamine has not been fully characterized and the effects of potent cytochrome P450 isoenzyme inhibition, such as the ketoconazole inhibition of CYP3A4, on fluvoxamine metabolism have not been studied.

Reciprocal interactions may occur with concomitant use of fomepizole and drugs that increase or inhibit the cytochrome P450 system (e.g., phenytoin, carbamazepine, cimetidine, ketoconazole), though this has not been studied.

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.

Although, fulvestrant is metabolized by CYP 3A4 in vitro , drug interactions studies with ketoconazole or rifampin did not alter fulvestrant pharmacokinetics.

In in vitro human microsomal studies, ketoconazole inhibited ring oxidation of granisetron hydrochloride. However, the clinical significance of in vivo pharmacokinetic interactions with ketoconazole is not known.

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).

Antivirals indinavir, maraviroc, saquinavir Beta Blockers nadolol Calcium Channel Blockers felodipine, nisoldipine other dihydropyridines, verapamil Calcium channel blockers can have a negative inotropic effect which may be additive to those of ketoconazole.

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.

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.

Although not observed in the lopinavir and ritonavir /ketoconazole drug interaction study, co-administration of lopinavir and ritonavir and other drugs that inhibit CYP3A may increase lopinavir plasma concentrations. 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.

7.4 Drugs without Clinically Significant Interactions with LIVTENCITY No clinically significant interactions were observed in clinical drug-drug interaction studies of LIVTENCITY and ketoconazole, antacid, caffeine, warfarin, voriconazole, dextromethorphan, or midazolam [see Clinical Pharmacology (12.3) ] .

Antivirals indinavir, maraviroc, saquinavir Beta Blockers nadolol Calcium Channel Blockers felodipine, nisoldipine other dihydropyridines, verapamil Calcium channel blockers can have a negative inotropic effect which may be additive to those of ketoconazole.

Drugs Dependent on Gastric pH for Absorption (e.g., iron salts, erlotinib, mycophenoloate mofetil, ketoconazole) Clinical Impact: Esomeprazole magnesium 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 magnesium 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.

CYP3A4 Inhibitors Concomitant use of AKYNZEO with a strong CYP3A4 inhibitor (e.g., ketoconazole) can increase the systemic exposure to the netupitant component of AKYNZEO.

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

In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A activity, to be at least 100 times more potent than fluoxetine or norfluoxetine as an inhibitor of the metabolism of several substrates for this enzyme, including astemizole, cisapride, and midazolam.

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 alter the absorption of other drugs due to its effect of reducing intragastric acidity thereby increasing gastric pH.

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.

In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and cyclosporine.

In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and cyclosporine.

In addition, in vitro studies have shown ketoconazole, a potent inhibitor of CYP3A4 activity, to be at least 100 times more potent than paroxetine as an inhibitor of the metabolism of several substrates for this enzyme, including terfenadine, astemizole, cisapride, triazolam, and cyclosporine.

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. posaconazole voriconazole ↑ rilpivirine ↓ ketoconazole Concomitant use of EDURANT or EDURANT PED with azole antifungal agents may cause an increase in the plasma concentrations of rilpivirine (inhibition of CYP3A enzymes).

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

Antivirals indinavir, maraviroc, saquinavir Beta Blockers nadolol Calcium Channel Blockers felodipine, nisoldipine other dihydropyridines, verapamil Calcium channel blockers can have a negative inotropic effect which may be additive to those of ketoconazole.

No dose adjustment for EMSAM is needed when EMSAM is used concomitantly with alcohol, alprazolam, ibuprofen, olanzapine, risperidone, levothyroxine, and CYP3A4 inhibitors (e.g., ketoconazole). No clinically meaningful change in selegiline exposure was seen when EMSAM was co-administered with alcohol, alprazolam, ibuprofen, olanzapine, risperidone, levothyroxine, and ketoconazole [see Clinical Pharmacology (12.3) ] . No dose adjustment of alprazolam, ibuprofen, levothyroxine, olanzapine, risperidone, warfarin, or strong CYP3A4 inhibitors (e.g., ketoconazole) is necessary when these drugs are used in combination with EMSAM.

7.4 Drugs without Clinically Significant Interactions with VOSEVI Based on drug interaction studies conducted with the components of VOSEVI (sofosbuvir, velpatasvir, and/or voxilaprevir) or VOSEVI, no clinically significant drug interactions have been observed with the following drugs [see Clinical Pharmacology (12.3) ]: VOSEVI: cobicistat, darunavir, elvitegravir, emtricitabine, ethinyl estradiol/norgestimate, gemfibrozil, rilpivirine, ritonavir, tenofovir alafenamide, voriconazole Sofosbuvir/velpatasvir: dolutegravir, ketoconazole, raltegravir Sofosbuvir: methadone, tacrolimus

Antibacterials rifabutin telithromycin Rifabutin: see also under 'Drugs that may decrease ketoconazole plasma concentrations' Telithromycin: A multiple-dose interaction study with ketoconazole showed that C max of telithromycin was increased by 51% and AUC by 95% Anticoagulants and Antiplatelet Drugs rivaroxaban cilostazol, coumarins, dabigatran Cilostazol: Concomitant administration of single doses of cilostazol 100 mg and ketoconazole 400 mg approximately doubled cilostazol concentrations and altered (increase/decrease) the concentrations of the active metabolites of cilostazol.

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

Drugs that have been documented not to interact with theophylline or drugs that produce no clinically significant interaction with theophylline.* albuterol, systemic and inhaled mebendazole amoxicillin medroxyprogesterone ampicillin, with or without methylprednisolone sulbactam metronidazole atenolol metoprolol azithromycin nadolol caffeine, dietary ingestion nifedipine cefaclor nizatidine co-trimoxazole (trimethoprim and sulfamethoxazole) norfloxacin ofloxacin diltiazem omeprazole dirithromycin prednisone, prednisolone enflurane ranitidine famotidine rifabutin felodipine roxithromycin finasteride Sorbitol (purgative doses do not inhibit hydrocortisone theophylline absorption) isoflurane sucralfate isoniazid terbutaline, systemic isradipine terfenadine influenza vaccine tetracycline ketoconazole tocainide lomefloxacin * Refer to PRECAUTIONS, Drug Interactions for information regarding table.

albuterol, systemic and inhaled mebendazole amoxicillin medroxyprogesterone ampicillin, with or without sulbactam methylprednisolone atenolol metronidazole azithromycin metoprolol caffeine, dietary ingestion nadolol cefaclor nifedipine co-trimoxazole (trimethoprim and sulfamethoxazole) nizatidine diltiazem norfloxacin dirithromycin ofloxacin enflurane omeprazole famotidine prednisone, prednisolone felodipine ranitidine finasteride rifabutin hydrocortisone roxithromycin isoflurane Sorbitol (purgative doses do not inhibit theophylline absorption) isoniazid sucralfate isradipine terbutaline, systemic influenza vaccine terfenadine ketoconazole tetracycline lomefloxacin tocainide

Simultaneous administration of drugs that inhibit the activity of liver microsomal enzymes, i.e., CYP3A4 inhibitors such as cimetidine and ketoconazole , may prolong the half-life and decrease the plasma clearance of tinidazole, increasing the plasma concentrations of tinidazole.

7.7 Inhibitors of Cytochrome P450 and P-gp Efflux Transporter In a drug interaction study using the strong dual CYP and P-gp inhibitor ketoconazole, a 1.7-fold increase of olodaterol maximum plasma concentrations and AUC was observed [see Pharmacokinetics (12.3) ] .

ketoconazole), protease inhibitors (e.g., ritonavir) CYP3A4 Inducers Clinical Impact: The concomitant use of tramadol hydrochloride extended-release tablets and CYP3A4 inducers can decrease the plasma concentration of tramadol [see Clinical Pharmacology (12.3)] , resulting in decreased efficacy or onset of a withdrawal syndrome in patients who have developed physical dependence to tramadol, [see Warnings and Precautions (5.7)] .

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

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

Velpatasvir: ethinyl estradiol/norgestimate, ketoconazole, or pravastatin.

Other Drugs (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Effect Vonoprazan reduces intragastric acidity [see Clinical Pharmacology (12.2) ] , which may decrease the absorption of drugs reducing their effectiveness. Other Drugs (e.g., iron salts, erlotinib, dasatinib, nilotinib, mycophenolate mofetil, ketoconazole/itraconazole) Clinical Effect Vonoprazan reduces intragastric acidity [see Clinical Pharmacology (12.2) ] , which may decrease the absorption of drugs reducing their effectiveness.

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 .

Other strong selective CYP3A4 inhibitors such as ketoconazole can also be expected to increase the exposure of zaleplon.

However, no formal drug-drug interaction studies between zileuton and CYP3A4 inhibitors, such as ketaconazole, have been conducted.