Fluconazole

Concomitant use increases systemic exposure of abrocitinib and active metabolites due to fluconazole's inhibition of CYP2C19, CYP2C9, and CYP3A4. Avoid concomitant use.

Physically incompatible with ceftriaxone in admixtures. Cannot be mixed in the same IV line.

Physically incompatible with ceftriaxone in admixtures. Must not be mixed in the same intravenous administration line.

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

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

Fluconazole increases fluvastatin exposure, increasing risk of myopathy and rhabdomyolysis. Avoid concomitant use.

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

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

Moderate dual CYP3A4 and CYP2C9 inhibitor predicted to increase macitentan exposure approximately 4-fold. Avoid co-administration.

Moderate dual CYP3A4 and CYP2C9 inhibitor predicted to increase macitentan exposure approximately 4-fold. Avoid concomitant use.

Moderate CYP 3A4 inhibitor; should not be co-administered with methylergonovine.

Moderate CYP 3A4 inhibitor; should not be co-administered with methylergonovine to avoid vasospasm risk.

( 7.1 , 12.3 ) Do not use fluconazole concomitantly with OSPHENA. Fluconazole increases serum concentrations of OSPHENA. 7.2 Fluconazole Do not use OSPHENA concomitantly with fluconazole, a moderate CYP3A / strong CYP2C9 / moderate CYP2C19 inhibitor.

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.

John's Wort (CYP450 inducer; P-gp inducer) Significantly Reduced Contraindicated Oral Contraceptives containing ethinyl estradiol and norethindrone (CYP2C19 Inhibition) Increased Monitoring for adverse reactions and toxicity related to voriconazole is recommended when coadministered with oral contraceptives Fluconazole (CYP2C9, CYP2C19 and CYP3A4 Inhibition) Significantly Increased Avoid concomitant administration of voriconazole and fluconazole. Monitoring for adverse reactions and toxicity related to voriconazole is started within 24 hours after the last dose of fluconazole Other HIV Protease Inhibitors (CYP3A4 Inhibition) In Vivo Studies Showed No Significant Effects of Indinavir on Voriconazole Exposure No dosage adjustment in the voriconazole dosage needed when coadministered with indinavir.

Moderate CYP2C9 and CYP3A inhibitor that increases aficamten exposure, potentially increasing risk of heart failure due to systolic dysfunction. Dose reduction or avoidance required.

Fluconazole reduces clearance and distribution volume of alfentanil and prolongs its half-life. Dosage adjustment may be necessary.

Concomitant administration may increase QT prolongation, particularly with high-dose fluconazole (800 mg). Caution required if concomitant use necessary.

As a CYP2C9 inhibitor, fluconazole combined with a strong or moderate CYP3A inhibitor will likely lead to large increases in bosentan plasma concentrations.

CYP2C9 inhibitor may enhance beta-blocking activity when used with carvedilol, resulting in further slowing of heart rate or cardiac conduction.

Moderate or strong CYP3A4 inhibitor; reduce EMFLAZA dose to one third of recommended dosage when used concomitantly.

Fluconazole increases fluvastatin exposure. Fluvastatin dose should be limited to 20 mg twice daily.

Inhibits metabolism of glimepiride, causing increased plasma concentrations and risk of severe hypoglycemia. Monitor closely.

Fluconazole increases glipizide AUC by mean 56.9% (range 35-81%), potentially increasing hypoglycemic effect. Close monitoring recommended.

Fluconazole increases glipizide AUC by a mean of 56.9%, potentially increasing hypoglycemic effect. Patient should be observed closely for hypoglycemia.

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

( 2.4 , 7.1 ) • Fluconazole : Avoid concomitant use; reduce LORBRENA dose if concomitant use cannot be avoided. Fluconazole Avoid concomitant use of LORBRENA with fluconazole. Concomitant use of LORBRENA with fluconazole may increase lorlatinib plasma concentrations [see Clinical Pharmacology (12.3) ] , which may increase the incidence and severity of adverse reactions of LORBRENA.

Avoid concomitant use of fluconazole with lemborexant Losartan: Fluconazole inhibits the metabolism of losartan to its active metabolite (E-31 74) which is responsible for most of the angiotensin II-receptor antagonism which occurs during treatment with losartan.

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

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

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

Moderate (e.g., fluconazole, atazanavir, aprepitant, diltiazem, erythromycin) and Strong (e.g., itraconazole, ketoconazole, clarithromycin, ritonavir, saquinavir) CYP3A Inhibitors Clinical Impact Increase in plasma naldemedine concentrations [see Clinical Pharmacology (12.3) ] Intervention Monitor for potential naldemedine-related adverse reactions [see Adverse Reactions (6.1) ] . Strong CYP3A inducers (e.g., rifampin) : Decreased naldemedine concentrations; avoid concomitant use ( 7 ) Other opioid antagonists : Potential for additive effect and increased risk of opioid withdrawal; avoid concomitant use ( 7 ) Moderate (e.g., fluconazole) and strong (e.g., itraconazole) CYP3A4 inhibitors : Increased naldemedine concentrations; monitor for adverse reactions ( 7 ) P-gp inhibitors (e.g., cyclosporine) : Monitor for adverse reactions ( 7 )

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

Fluconazole, posaconazole and itraconazole : Avoid concomitant use with TALICIA.

DRUG INTERACTIONS Fluconazole: Avoid concomitant use with fluconazole doses greater than 200 mg. Reduce Jakafi dosage with fluconazole doses less than or equal to 200 mg. ( 2.6 , 7 ) 7.1 Effect of Other Drugs on Jakafi Fluconazole Concomitant use of Jakafi with fluconazole increases ruxolitinib exposure [ see Clinical Pharmacology ( 12.3 )] , which may increase the risk of exposure-related adverse reactions.

7 DRUG INTERACTIONS • Strong or Moderate CYP3A4 Inhibitors or Fluconazole : Avoid coadministration of strong or moderate CYP3A4 inhibitors or fluconazole with KOSELUGO. ( 7.1 ) 7.1 Effect of Other Drugs on KOSELUGO Strong or Moderate CYP3A4 Inhibitors or Fluconazole Management • Avoid concomitant use of strong or moderate CYP3A4 inhibitors or fluconazole with KOSELUGO. If coadministration with strong or moderate CYP3A4 inhibitors or fluconazole cannot be avoided, reduce KOSELUGO dosage [see Dosage and Administration (2.4) ].

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

CYP3A inhibitor that causes earlier onset and/or increased severity of neuromuscular side effects. Moderate CYP3A inhibitor requiring frequent monitoring if used concurrently.

CYP2C9 inhibitor that increases warfarin effect and INR; requires close INR monitoring

CYP2C9 inhibitor that increases warfarin effect and INR; requires closer INR monitoring.

Fluconazole increases the effect of amitriptyline. Dosage adjustment may be necessary; monitor plasma levels.

Fluconazole has potential to increase systemic exposure of amlodipine. Frequent monitoring for adverse effects recommended.

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.

Moderate CYP3A4 inhibitors (e.g., erythromycin, amprenavir, aprepitant, diltiazem, fluconazole, fosamprenavir, and verapamil) would be expected to have similar effects.

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

Concomitant administration of fluconazole (a CYP2C9 inhibitor) may increase celecoxib plasma levels due to inhibition of celecoxib metabolism.

Cimetidine 400 mg decreased fluconazole AUC by 13% and Cmax by 19%. Intravenous cimetidine 600-900 mg had no effect on fluconazole bioavailability.

CYP2C19 inhibitor increases risk of QT prolongation. Maximum recommended citalopram dosage is 20 mg daily.

Dosage adjustment of clobazam oral suspension may be necessary when co-administered with strong CYP2C19 inhibitors (e.g., fluconazole, fluvoxamine, ticlopidine) or moderate CYP2C19 inhibitors (e.g., omeprazole) [see Clinical Pharmacology ( 12.3 )].

Should be used cautiously as it may impair clonazepam metabolism leading to exaggerated concentrations and effects.

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

Increases cyclosporine concentrations via CYP3A4 inhibition. Dosage adjustment essential.

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

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

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

Administer moderate CYP3A4 inhibitors (e.g., saquinavir, nefazodone, fluconazole, grapefruit juice, fluoxetine, fluvoxamine, zileuton, clotrimazole) with caution.

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

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

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

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

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

Concomitant use of fluconazole increased ivacaftor AUC by 2.9-fold [see Clinical Pharmacology (12.3) ] . Examples of moderate CYP3A inhibitors include: fluconazole erythromycin Grapefruit Concomitant use of TRIKAFTA with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of elexacaftor, tezacaftor and ivacaftor; therefore, food or drink containing grapefruit should be avoided during treatment with TRIKAFTA [see Dosage and Administration (2.4) ] .

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

[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.

Fluconazole 200 mg increased ethinyl estradiol AUC by 38% and fluconazole 300 mg increased it by 24%. Fluconazole 50 mg showed no significant effect.

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.

Moderate to Strong Inhibitors of CYP2C9 and CYP3A4 Clinical Impact Increased exposure of etrasimod was observed with concomitant use with a drug that is a moderate inhibitor of CYP2C9 and a moderate inhibitor of CYP3A4 (i.e., fluconazole) [see Clinical Pharmacology (12.3) ] .

Antifungals : fluconazole voriconazole ↑ etravirine ↔ fluconazole voriconazole Co-administration of etravirine and fluconazole significantly increased etravirine exposures. The amount of safety data at these increased etravirine exposures is limited, therefore, etravirine and fluconazole should be co-administered with caution. No dose adjustment of etravirine tablets or fluconazole is needed.

7.10 Other Possible Interactions Moderate inhibitors of CYP3A4 and P-gp may increase everolimus blood concentrations (e.g., fluconazole; macrolide antibiotics; nicardipine, diltiazem; nelfinavir, indinavir, amprenavir).

7.10 Other Possible Interactions Moderate inhibitors of CYP3A4 and P-gp may increase everolimus blood concentrations (e.g., fluconazole; macrolide antibiotics; nicardipine, diltiazem; nelfinavir, indinavir, amprenavir).

Fluconazole has potential to increase systemic exposure of felodipine. Frequent monitoring for adverse effects recommended.

Following blockade of CYP3A4 by coadministration of the moderate CYP3A4 inhibitor fluconazole 200 mg twice a day for 2 days, the average (90% confidence interval) increase in C max and AUC of the active metabolite of fesoterodine was approximately 19% (11% to 28%) and 27% (18% to 36%) respectively. No dosing adjustments are recommended in the presence of moderate CYP3A4 inhibitors (e.g., erythromycin, fluconazole, diltiazem, verapamil and grapefruit juice).

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

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)]

Ibrutinib : Moderate inhibitors of CYP3A4 such as fluconazole may increase plasma ibrutinib concentrations and increase risk of adverse reactions associated with ibrutinib. If ibrutinib and fluconazole are concomitantly administered, reduce the dose of ibrutinib as instructed in ibrutinib prescribing information and the patient should be frequently monitored for any adverse reactions associated with ibrutinib.

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

Fluconazole has potential to increase systemic exposure of isradipine. Frequent monitoring for adverse effects recommended.

7 DRUG INTERACTIONS Potential for other drugs to affect ivacaftor CYP3A inhibitors: Reduce KALYDECO dosage in patients aged 6 months and older when co-administered with strong CYP3A inhibitors (e.g., ketoconazole) or moderate CYP3A inhibitors (e.g., fluconazole). Co-administration with fluconazole, a moderate inhibitor of CYP3A, increased ivacaftor exposure by 3-fold. Therefore, a reduction of the KALYDECO dosage is recommended for patients aged 6 months and older taking concomitant moderate CYP3A inhibitors, such as fluconazole and erythromycin.

Fluconazole 200 mg increased levonorgestrel AUC by 25%. Fluconazole 50 mg showed no significant difference.

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

CYP3A4 inhibitor may increase plasma hormone concentrations.

CYP3A inhibitor that may increase systemic exposure of estrogen component.

Decreased AUC of active metabolite by approximately 40% but increased AUC of losartan by approximately 70%.

Fluconazole decreased active metabolite AUC by approximately 40% but increased losartan AUC by approximately 70%. Pharmacodynamic consequences not fully examined.

CYP3A4 inhibitor that significantly increases midazolam C max and AUC, resulting in increased and prolonged sedation.

CYP2C9 inhibitor that may increase blood-glucose-lowering effect and susceptibility to hypoglycemia. Dose reductions and increased glucose monitoring may be required.

Antifungals: Fluconazole* ↑Nevirapine Because of the risk of increased exposure to nevirapine, caution should be used in concomitant administration, and patients should be monitored closely for nevirapine-associated adverse events.

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

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.

May increase plasma hormone concentrations.

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.

Fluconazole increases the effect of nortriptyline. Dosage adjustment may be necessary; monitor plasma levels.

Monitor patients concomitantly receiving moderate CYP3A4 inhibitors (e.g., fluconazole) for increased adverse reactions and consider VONJO dose modifications based on safety [see Dosage and Administration ( 2.5 )] . Concomitant use of VONJO with doses of fluconazole greater than 200 mg once daily has not been studied.

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

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.

CYP2C19 substrate/inhibitor that may increase blood levels and/or toxicity of propranolol.

( 7.1 ) Fluconazole (strong CYP2C9 inhibitor): Increases systemic exposure of ramelteon; administer with caution. Fluconazole (strong CYP2C9 inhibitor) The AUC 0-inf and C max of ramelteon was increased by approximately 150% when ramelteon was coadministered with fluconazole. Ramelteon should be administered with caution in subjects taking strong CYP2C9 inhibitors such as fluconazole [see Clinical Pharmacology (12.5) ] .

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

Weak/moderate CYP3A4/P-gp inhibitor that may increase sirolimus concentrations. Monitor and adjust dosage as needed.

Therefore, carefully monitor for rifabutin associated adverse events in those patients also receiving CYP3A inhibitors, which include fluconazole and clarithromycin. ANTIFUNGALS Fluconazole 200 mg once a day for 2 weeks 300 mg once a day for 2 weeks HIV infected patients (12) ↑ AUC by 82%, ↑ C max by 88% Monitor for rifabutin associated adverse events.

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

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

Dual Moderate CYP2C9 and Moderate or Strong CYP3A4 Inhibitors (e.g., fluconazole) ↑ seladelpar Monitor patients for adverse effects during concomitant use of LIVDELZI with drugs that are dual moderate CYP2C9 and moderate or strong CYP3A4 inhibitors.

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

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

Fluconazole increases terbinafine Cmax by 52% and AUC by 69%. Inhibitor of CYP2C9 and CYP3A enzymes.

Fluconazole increases terbinafine Cmax by 52% and AUC by 69%. Fluconazole inhibits CYP2C9 and CYP3A enzymes affecting terbinafine metabolism.

Fluconazole increases terbinafine Cmax by 52% and AUC by 69%. Coadministration requires monitoring.

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. Simulation suggested co-administration with fluconazole, a moderate CYP3A inhibitor, may increase tezacaftor exposure (AUC) by approximately 2.0-fold.

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.

CYP2C9 inhibitor that decreases torsemide clearance and increases plasma concentrations; monitor diuretic effect and blood pressure.

Dose adjustment is recommended with concomitant use of UBRELVY and moderate CYP3A4 inhibitors (e.g., cyclosporine, ciprofloxacin, fluconazole, fluvoxamine, grapefruit juice) [see Dosage and Administration ( 2.2 )] .

Fluconazole has potential to increase systemic exposure of verapamil. Frequent monitoring for adverse effects recommended.

Reduce LUPKYNIS dosage when co-administered with moderate CYP3A4 inhibitors (e.g., verapamil, fluconazole, diltiazem) [see Dosage and Administration ( 2.5 ] .

Coadministration of zafirlukast with fluconazole, a moderate CYP2C9 inhibitor, resulted in increased plasma levels of zafirlukast, by approximately 58% (90% CI:28, 95).

No significant pharmacokinetic interaction between fluconazole and azithromycin observed in a three-way crossover study.

Has been used with busulfan; decreased clearance of busulfan observed with concomitant use.

Co-administration with micafungin did not alter fluconazole pharmacokinetics.

Co-administration did not show clinically significant effect on treprostinil pharmacokinetics.

7.4 Drugs with No Observed Interactions with REYATAZ No clinically significant drug interactions were observed when REYATAZ was coadministered with methadone, fluconazole, acetaminophen, atenolol, or the nucleoside reverse transcriptase inhibitors lamivudine or zidovudine [see Clinical Pharmacology, Tables 21 and 22 (12.3) ] .

7.4 Drugs with No Observed or Predicted Interactions with the Components of EVOTAZ Based on known metabolic profiles, clinically significant drug interactions are not expected between EVOTAZ and acetaminophen, atenolol, dapsone, fluconazole, trimethoprim/sulfamethoxazole, or azithromycin [see Clinical Pharmacology (12.3; Table 7) ].

7.4 Drugs with No Observed Interactions with Atazanavir No clinically significant drug interactions were observed when atazanavir was coadministered with methadone, fluconazole, acetaminophen, atenolol, or the nucleoside reverse transcriptase inhibitors lamivudine or zidovudine [see Clinical Pharmacology, Tables 21 and 22 ( 12.3 )] .

HMG-CoA reductase inhibitors : The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolized through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin.

The concomitant administration of amiodarone or other CYP2C9 inhibitors such as fluconazole with carvedilol phosphate extended-release capsules may enhance the beta-blocking activity, resulting in further slowing of the heart rate or cardiac conduction.

7.4 Drug-Drug Interaction Studies Four pharmacokinetic studies evaluated the effects of co-administration of voriconazole (200 mg BID), fluconazole (200 mg QD), cimetidine (800 mg BID), and propafenone (225 mg BID) on systemic levels of colchicine.

) Cyclophosphamide : Combination therapy with cyclophosphamide and fluconazole results in an increase in serum bilirubin and serum creatinine.

7.5 Drugs Without Clinically Significant Interactions with Efavirenz No dosage adjustment is recommended when efavirenz is given with the following: aluminum/magnesium hydroxide antacids, azithromycin, cetirizine, famotidine, fluconazole, lorazepam, nelfinavir, nucleoside reverse transcriptase inhibitors (abacavir, emtricitabine, lamivudine, stavudine, tenofovir disoproxil fumarate, zidovudine), paroxetine, and raltegravir.

7.6 Drugs without Clinically Significant Interactions No dosage adjustment is recommended when efavirenz, lamivudine and tenofovir disoproxil fumarate is administered with the following: aluminum/magnesium hydroxide antacids, azithromycin, cetirizine, famotidine, fluconazole, and lorazepam.

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

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

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

CYP450 Inhibitors Examples (not fully inclusive): Clarithromycin, itraconazole, voriconazole, erythromycin, fluconazole Clinical Impact Multiple CYP450 enzymes are involved in the metabolism of fexinidazole to its pharmacologically active M1 and M2 metabolites.

Hydrochlorothiazide: Concomitant oral administration of 100 mg fluconazole and 50 mg hydrochlorothiazide for 10 days in 13 normal volunteers resulted in a significant increase in fluconazole AUC and C max compared to fluconazole given alone. Hydrochlorothiazide : In a pharmacokinetic interaction study, coadministration of multiple-dose hydrochlorothiazide to healthy volunteers receiving fluconazole increased plasma concentrations of fluconazole by 40%.

Fluconazole No Dose Adjustment Fluconazole : No dosage adjustment of clarithromycin is necessary when coadministered with fluconazole.

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

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

Consider an alternative such as fluconazole.

Thus concomitant usage of CYP2C9 inhibitors (such as amiodarone, fluconazole, and sulphaphenazole) may lead to abnormally high plasma levels of meloxicam due to reduced metabolic clearance [see Use in Specific Populations (8.8); and Clinical Pharmacology ( 12.3 , 12.5 ) ].

Thus, concomitant usage of CYP2C9 inhibitors (e.g., amiodarone, fluconazole) may lead to abnormally high plasma levels of meloxicam due to reduced metabolic clearance [see Use in Specific Populations (8.8) , Clinical Pharmacology (12.3, 12.5)] .

( 7 ) 7.1 Effect of Other Drugs on Micafungin CYP3A4, CYP2C9 and CYP2C19 Inhibitors Co-administration of micafungin with cyclosporine, itraconazole, voriconazole and fluconazole did not alter the pharmacokinetics of micafungin. 7.2 Effect of Micafungin on Other Drugs CYP3A4 Substrates There was no effect of single or multiple doses of micafungin on cyclosporine, tacrolimus, prednisolone, voriconazole and fluconazole pharmacokinetics.

(See PRECAUTIONS .) Midazolam: The effect of fluconazole on the pharmacokinetics and pharmacodynamics of midazolam was examined in a randomized, cross-over study in 12 volunteers. In addition, a 7.5 mg dose of midazolam was orally ingested on the first day, 0.05 mg/kg was administered intravenously on the fourth day, and 7.5 mg orally on the sixth day. Fluconazole reduced the clearance of IV midazolam by 51%.

The following are examples of medications that may increase the glucose-lowering effect of sulfonylureas including glimepiride, a component of pioglitazone and glimepiride tablets, increasing the susceptibility to and/or intensity of hypoglycemia: oral anti-diabetic medications, pramlintide acetate, insulin, angiotensin converting enzyme (ACE) inhibitors, H2 receptor antagonists, fibrates, propoxyphene, pentoxifylline, somatostatin analogs, anabolic steroids and androgens, cyclophosphamide, phenyramidol, guanethidine, fluconazole, sulfinpyrazone, tetracyclines, clarithromycin, disopyramide, quinolones, and those drugs that are highly protein-bound, such as fluoxetine, nonsteroidal anti-inflammatory drugs, salicylates, sulfonamides, chloramphenicol, coumarins, probenecid and monoamine oxidase inhibitors. 7.6 CYP2C9 Interactions Glimepiride There may be an interaction between glimepiride and inhibitors (e.g., fluconazole) and inducers (e.g., rifampin) of CYP2C9. Fluconazole may inhibit the metabolism of glimepiride, causing increased plasma concentrations of glimepiride which may lead to hypoglycemia.

Drug-Drug Interactions Table 3: Effect of Coadministered Drugs on the Pharmacokinetics of Pravastatin Pravastatin Coadministered Drug and Dosing Regimen Dose (mg) Change in AUC Change in C max BID = twice daily; OD = once daily; QID = four times daily Cyclosporine 5 mg/kg single dose 40 mg single dose ↑282% ↑327% Clarithromycin 500 mg BID for 9 days 40 mg OD for 8 days ↑110% ↑128% Boceprevir 800 mg TID for 6 days 40 mg single dose ↑63% ↑49% Darunavir 600 mg BID/Ritonavir 100 mg BID for 7 days 40 mg single dose ↑81% ↑63% Colestipol 10 g single dose 20 mg single dose ↓47% ↓53% Cholestyramine 4 g single dose Administered simultaneously Administered 1 hour prior to cholestyramine Administered 4 hours after cholestyramine 20 mg single dose ↓40% ↑12% ↓12% ↓39% ↑30% ↓6.8% Cholestyramine 24 g OD for 4 weeks 20 mg BID for 8 weeks 5 mg BID for 8 weeks 10 mg BID for 8 weeks ↓51% ↓38% ↓18% ↑4.9% ↑23% ↓33% Fluconazole 200 mg IV for 6 days 200 mg PO for 6 days 20 mg PO+10 mg IV 20 mg PO+10 mg IV ↓34% ↓16% ↓33% ↓16% Kaletra 400 mg/100 mg BID for 14 days 20 mg OD for 4 days ↑33% ↑26% Verapamil IR 120 mg for 1 day and Verapamil ER 480 mg for 3 days 40 mg single dose ↑31% ↑42% Cimetidine 300 mg QID for 3 days 20 mg single dose ↑30% ↑9.8% Antacids 15 mL QID for 3 days 20 mg single dose ↓28% ↓24% Digoxin 0.2 mg OD for 9 days 20 mg OD for 9 days ↑23% ↑26% Probucol 500 mg single dose 20 mg single dose ↑14% ↑24% Warfarin 5 mg OD for 6 days 20 mg BID for 6 days ↓13% ↑6.7% Itraconazole 200 mg OD for 30 days 40 mg OD for 30 days ↑11% (compared to Day 1) ↑17% (compared to Day 1) Gemfibrozil 600 mg single dose 20 mg single dose ↓7.0% ↓20% Aspirin 324 mg single dose 20 mg single dose ↑4.7% ↑8.9% Niacin 1 g single dose 20 mg single dose ↓3.6% ↓8.2% Diltiazem 20 mg single dose ↑2.7% ↑30% Grapefruit juice 40 mg single dose ↓1.8% ↑3.7% Table 4: Effect of Pravastatin on the Pharmacokinetics of Coadministered Drugs Pravastatin Dosing Regimen Name and Dose Change in AUC Change in C max BID = twice daily; OD = once daily 20 mg BID for 6 days Warfarin 5 mg OD for 6 days Change in mean prothrombin time ↑17% ↑0.4 sec ↑15% 20 mg OD for 9 days Digoxin 0.2 mg OD for 9 days ↑4.6% ↑5.3% 20 mg BID for 4 weeks 10 mg BID for 4 weeks 5 mg BID for 4 weeks Antipyrine 1.2 g single dose ↑3.0% ↑1.6% ↑ Less than 1% Not Reported 20 mg OD for 4 days Kaletra 400 mg/100 mg BID for 14 days No change No change

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.

(See CLINICAL PHARMACOLOGY: Drug Interaction Studies .) Saquinavir : Fluconazole increases the AUC of saquinavir by approximately 50%, C max by approximately 55%, and decreases the clearance of saquinavir by approximately 50% due to inhibition of saquinavir’s hepatic metabolism by CYP3A4 and inhibition of P-glycoprotein. Dosage adjustment of saquinavir may be necessary.

HMG-CoA reductase inhibitors : The risk of myopathy and rhabdomyolysis increases when fluconazole is coadministered with HMG-CoA reductase inhibitors metabolized through CYP3A4, such as atorvastatin and simvastatin, or through CYP2C9, such as fluvastatin.

Agents for Opportunistic Infections Antifungals: Fluconazole Itraconazole Ketoconazole ↑ Tipranavir, ↔ Fluconazole Fluconazole increases tipranavir concentrations but dose adjustments are not needed. Fluconazole doses >200 mg/day are not recommended.

(See CONTRAINDICATIONS and PRECAUTIONS .) Oral hypoglycemics: The effects of fluconazole on the pharmacokinetics of the sulfonylurea oral hypoglycemic agents tolbutamide, glipizide, and glyburide were evaluated in three placebo-controlled studies in normal volunteers. (See PRECAUTIONS .) Tolbutamide: In 13 normal male volunteers, there was significant increase in tolbutamide (500 mg single dose) AUC and C max following the administration of fluconazole. There was a mean ± SD increase in tolbutamide AUC of 26% ± 9% (range: 12 to 39%).

Triazolam: Fluconazole increases the AUC of triazolam (single dose) by approximately 50%, C max by 20% to 32%, and increases t ½ by 25% to 50% due to the inhibition of metabolism of triazolam. Dosage adjustments of triazolam may be necessary.