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Ketoconazole (Systemic)

Pronunciation

Pronunciation

(kee toe KOE na zole)

Index Terms

  • Nizoral

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Generic: 200 mg

Pharmacologic Category

  • Antifungal Agent, Imidazole Derivative
  • Antifungal Agent, Oral

Pharmacology

Alters the permeability of the cell wall by blocking fungal cytochrome P450; inhibits biosynthesis of triglycerides and phospholipids by fungi; inhibits several fungal enzymes that results in a build-up of toxic concentrations of hydrogen peroxide; for management of prostate cancer, ketoconazole inhibits androgen synthesis

Distribution

Well into inflamed joint fluid, saliva, bile, urine, sebum, cerumen, feces, tendons, skin and soft tissue, and testes; crosses blood-brain barrier poorly; only negligible amounts reach CSF

Metabolism

Partially hepatic via CYP3A4 to inactive metabolites

Excretion

Feces (57%); urine (13%)

Time to Peak

Serum: 1-2 hours

Half-Life Elimination

Biphasic: Initial: 2 hours; Terminal: 8 hours

Protein Binding

~99% (mainly albumin)

Use: Labeled Indications

Fungal infections (systemic):

US labeling: Treatment of susceptible systemic fungal infections, including blastomycosis, histoplasmosis, paracoccidioidomycosis, coccidioidomycosis, and chromomycosis in patients who have failed or who are intolerant to other antifungal therapies

Limitations of use: Ketoconazole should only be used when other effective antifungal therapy is not available or tolerated and the potential benefits outweigh the potential risks.

Canadian labeling: Treatment of serious or life-threatening systemic fungal infections (eg, systemic candidiasis, chronic mucocutaneous candidiasis, coccidioidomycosis, paracoccidioidomycosis, histoplasmosis, and chromomycosis) where alternate therapy is inappropriate or ineffective; may be considered for severe dermatophytoses unresponsive to other therapy

Use: Unlabeled

Treatment of advanced prostate cancer

Contraindications

Hypersensitivity to ketoconazole or any component of the formulation; acute or chronic liver disease; coadministration with alprazolam, cisapride, colchicine, disopyramide, dofetilide, dronedarone, eplerenone, ergot alkaloids (eg, dihydroergotamine, ergometrine, ergotamine, methylergometrine), felodipine, HMG-CoA reductase inhibitors (eg, lovastatin, simvastatin), irinotecan, lurasidone, methadone, oral midazolam, nisoldipine, pimozide, quinidine, ranolazine, tolvaptan, triazolam

Canadian labeling: Additional contraindications (not in U.S. labeling): Women of childbearing potential unless effective forms of contraception are used; coadministration with astemizole or terfenadine

Dosing: Adult

Fungal infections (systemic): Oral: 200 mg once daily; may increase to 400 mg once daily if response is insufficient. Continue until active fungal infection is resolved; some infections may require a treatment duration of up to 6 months.

Prostate cancer, advanced (off-label use): Oral: 400 mg 3 times daily (in combination with oral hydrocortisone) until disease progression (Ryan 2007; Small 2004)

Cushing syndrome (off-label use): Oral: Initial: 400 to 600 mg daily in 2 or 3 divided doses; may increase dose by 200 mg daily every 7 to 28 days up to a maximum of 1,200 mg daily in 2 or 3 divided doses; dosage range: 200 to 1,200 mg daily; mean effective dose in most studies: 600 to 800 mg daily in 2 divided doses (Castinetti 2014; ES [Nieman 2015]; Miller 1993)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Fungal infections (systemic): Children >2 years: Oral: 3.3 to 6.6 mg/kg once daily. Continue until active fungal infection is resolved; some infections may require a treatment duration of up to 6 months.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling. However, some resources suggest that no dosage adjustment is necessary in mild-to-severe impairment (Aronoff 2007).

End-stage renal disease (ESRD) on intermittent hemodialysis: Supplemental dose is not necessary (Aronoff 2007). Not dialyzable.

Dosing: Hepatic Impairment

Use is contraindicated in acute or chronic liver disease.

Hepatotoxicity during treatment:

US labeling: If ALT >ULN or 30% above baseline (or if patient is symptomatic), interrupt therapy and obtain full hepatic function panel. Upon normalization of liver function, may consider resuming therapy if benefit outweighs risk (hepatotoxicity has been reported on rechallenge).

Canadian labeling: Discontinue therapy for liver function tests >3 times ULN or if abnormalities persist, worsen, or are associated with hepatotoxicity symptoms.

Extemporaneously Prepared

A 20 mg/mL oral suspension may be made with tablets and one of three different vehicles (a 1:1 mixture of Ora-Sweet® and Ora-Plus®, a 1:1 mixture of Ora-Sweet® SF and Ora-Plus®, or a 1:4 mixture of cherry syrup and Simple Syrup, NF). Crush twelve 200 mg tablets in a mortar and reduce to a fine powder. Add 20 mL of chosen vehicle and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 120 mL. Label “shake well” and “refrigerate”. Stable for 60 days.

Nahata MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.

Administration

Administer oral tablets 2 hours prior to antacids to prevent decreased absorption due to the high pH of gastric contents. Patients with achlorhydria should administer with acidic liquid (eg, soda pop).

Dietary Considerations

May be taken with food or milk to decrease GI adverse effects.

Storage

Store at 15°C to 25°C (59°F to 77°F). Protect from light and moisture.

Drug Interactions

Ado-Trastuzumab Emtansine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Ado-Trastuzumab Emtansine. Specifically, strong CYP3A4 inhibitors may increase concentrations of the cytotoxic DM1 component. Avoid combination

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Alcohol (Ethyl): Ketoconazole (Systemic) may enhance the adverse/toxic effect of Alcohol (Ethyl). Management: Advise patients to avoid alcohol ingestion while taking ketoconazole. Consider therapy modification

Alfuzosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alfuzosin. Avoid combination

Aliskiren: Ketoconazole (Systemic) may increase the serum concentration of Aliskiren. Monitor therapy

Alitretinoin (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alitretinoin (Systemic). Management: Consider reducing the alitretinoin dose to 10 mg when used together with strong CYP3A4 inhibitors. Monitor for increased alitretinoin effects/toxicities if combined with a strong CYP3A4 inhibitor. Consider therapy modification

Almotriptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Almotriptan. Management: Limit initial almotriptan adult dose to 6.25 mg and maximum adult dose to 12.5 mg/24-hrs when used with a strong CYP3A4 inhibitor. Avoid concurrent use in patients with impaired hepatic or renal function. Consider therapy modification

Alosetron: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Alosetron. Monitor therapy

ALPRAZolam: Ketoconazole (Systemic) may increase the serum concentration of ALPRAZolam. Avoid combination

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Amphotericin B: Antifungal Agents (Azole Derivatives, Systemic) may diminish the therapeutic effect of Amphotericin B. Monitor therapy

Antacids: May decrease the serum concentration of Ketoconazole (Systemic). Management: Administer oral ketoconazole at least 2 hours prior to use of any antacid product. Monitor patients closely for signs of inadequate clinical response to ketoconazole. Consider therapy modification

Antihepaciviral Combination Products: May increase the serum concentration of Ketoconazole (Systemic). Ketoconazole (Systemic) may increase the serum concentration of Antihepaciviral Combination Products. Specifically, ketoconazole may increase serum concentrations of paritaprevir. Management: Limit the dose of ketoconazole to 200 mg per day in patients taking antihepaciviral combination products. Additionally, monitor for increased ketoconazole effects/toxicities and for increased paritaprevir effects/toxicities. Consider therapy modification

Apixaban: Inhibitors of CYP3A4 (Strong) and P-glycoprotein may increase the serum concentration of Apixaban. Management: US labeling recommends a 50% apixaban dose reduction in patients who would otherwise receive 5 or 10 mg twice daily, and avoiding in patients who would otherwise receive 2.5 mg twice daily. Canadian labeling lists any combined use as contraindicated. Consider therapy modification

Aprepitant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Aprepitant. Avoid combination

ARIPiprazole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of ARIPiprazole. Management: See full interaction monograph for details. Consider therapy modification

ARIPiprazole Lauroxil: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Please refer to the full interaction monograph for details concerning the recommended dose adjustments. Consider therapy modification

Artesunate: CYP2A6 Inhibitors may decrease serum concentrations of the active metabolite(s) of Artesunate. CYP2A6 Inhibitors may increase the serum concentration of Artesunate. Avoid combination

Astemizole: Ketoconazole (Systemic) may enhance the QTc-prolonging effect of Astemizole. Ketoconazole (Systemic) may increase the serum concentration of Astemizole. Avoid combination

Asunaprevir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Asunaprevir. Avoid combination

AtorvaSTATin: May enhance the adverse/toxic effect of Ketoconazole (Systemic). Specifically, there is a theoretical potential for additive effects on reducing endogenous steroid concentrations. Ketoconazole (Systemic) may increase the serum concentration of AtorvaSTATin. Management: Administer ketoconazole with atorvastatin cautiously, and monitor for toxic effects of atorvastatin (e.g., myalgia, rhabdomyolysis, liver function test abnormalities). Consider use of fluva-, rosuva-, pitava-, or pravastatin when possible. Consider therapy modification

Avanafil: Ketoconazole (Systemic) may increase the serum concentration of Avanafil. Avoid combination

Axitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Axitinib. Management: Avoid concurrent use of axitinib with any strong CYP3A inhibitor whenever possible. If a strong CYP3A inhibitor must be used with axitinib, a 50% axitinib dose reduction is recommended. Avoid combination

Barnidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Barnidipine. Avoid combination

Bedaquiline: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bedaquiline. Management: Limit the duration of concomitant administration of bedaquiline with CYP3A4 inhibitors to no more than 14 days, unless the benefit of continued administration is judged to outweigh the possible risks. Monitor for toxic effects of bedaquiline. Consider therapy modification

Blonanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Blonanserin. Avoid combination

Boceprevir: Ketoconazole (Systemic) may increase the serum concentration of Boceprevir. Boceprevir may increase the serum concentration of Ketoconazole (Systemic). Management: Limit maximum adult ketoconazole dose to 200 mg daily in patients receiving boceprevir, due to a possible increase in ketoconazole concentrations. Consider therapy modification

Bortezomib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bortezomib. Monitor therapy

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Bosentan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Bosentan: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Bosentan. Management: Concomitant use of both a CYP2C9 inhibitor and a CYP3A inhibitor or a single agent that inhibits both enzymes with bosentan is likely to cause a large increase in serum concentrations of bosentan and is not recommended. See monograph for details. Monitor therapy

Bosutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bosutinib. Avoid combination

Bosutinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bosutinib. Avoid combination

Brentuximab Vedotin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Brexpiprazole: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose to 50% of usual with a strong CYP3A4 inhibitor; reduce to 25% of usual if used with both a moderate CYP3A4 inhibitor and a CYP2D6 inhibitor, or if a strong CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer. Consider therapy modification

Brinzolamide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Brinzolamide. Monitor therapy

Bromocriptine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Bromocriptine. Avoid combination

Budesonide (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Nasal). Monitor therapy

Budesonide (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Oral Inhalation). Monitor therapy

Budesonide (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Systemic). Avoid combination

Budesonide (Topical): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Budesonide (Topical). Management: Per US prescribing information, avoid this combination. Canadian product labeling does not recommend strict avoidance. If combined, monitor for excessive glucocorticoid effects as budesonide exposure may be increased. Consider therapy modification

BusPIRone: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of BusPIRone. Isavuconazonium considerations are addressed in separate monographs. Consider therapy modification

Busulfan: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Busulfan. Isavuconazonium considerations are addressed in separate monographs. Monitor therapy

Cabazitaxel: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cabazitaxel. Management: Concurrent use of cabazitaxel with strong inhibitors of CYP3A4 should be avoided when possible. If such a combination must be used, consider a 25% reduction in the cabazitaxel dose. Consider therapy modification

Cabozantinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cabozantinib. Management: Avoid use of a strong CYP3A4 inhibitor with cabozantinib if possible. If combined, cabozantinib dose adjustments are recommended and vary based on the cabozantinib product used and the indication for use. See monograph for details. Consider therapy modification

Calcifediol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Calcifediol. Monitor therapy

Calcium Channel Blockers: Antifungal Agents (Azole Derivatives, Systemic) may enhance the adverse/toxic effect of Calcium Channel Blockers. Specifically, itraconazole may enhance the negative inotropic effects of verapamil or diltiazem. Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Calcium Channel Blockers. Fluconazole and isavuconazonium likely exert weaker effects than other azoles and are addressed in separate monographs. Management: Concurrent use of felodipine or nisoldipine with itraconazole is specifically contraindicated. Frequent monitoring is warranted with any such combination; calcium channel blocker dose reductions may be required. Exceptions: Clevidipine. Consider therapy modification

Cannabis: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol serum concentrations may be increased. Monitor therapy

Cannabis: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cannabis. More specifically, tetrahydrocannabinol and cannabidiol serum concentrations may be increased. Monitor therapy

Carbocisteine: Ketoconazole (Systemic) may enhance the adverse/toxic effect of Carbocisteine. Specifically, ketoconazole may enhance adverse effects of alcohol that is present in liquid formulations of carbocisteine-containing products. Management: Advise patients to avoid alcohol ingestion while taking ketoconazole. Liquid formulations of carbcisteine-containing products contain alcohol, which may interact with ketoconazole in some patients. Consider therapy modification

Cariprazine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cariprazine. Management: Cariprazine dose reductions of 50% are required; specific recommended management varies slightly for those stable on cariprazine versus those just starting cariprazine. See prescribing information or full interaction monograph for details. Consider therapy modification

Carvedilol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Carvedilol. Specifically, concentrations of the S-carvedilol enantiomer may be increased. Monitor therapy

Ceritinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ceritinib. Management: If such combinations cannot be avoided, the ceritinib dose should be reduced by approximately one-third (to the nearest 150 mg). Resume the prior ceritinib dose after cessation of the strong CYP3A4 inhibitor. Avoid combination

Choline C 11: Antiandrogens may diminish the therapeutic effect of Choline C 11. Monitor therapy

Cilostazol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in adult patients who are also receiving strong inhibitors of CYP3A4. Consider therapy modification

Cilostazol: CYP2C19 Inhibitors may increase the serum concentration of Cilostazol. Management: Consider reducing the cilostazol dose to 50 mg twice daily in patients who are also receiving inhibitors of CYP2C19. Consider therapy modification

Cisapride: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Cisapride. Isavuconazonium considerations are addressed in separate monographs. Avoid combination

Citalopram: CYP2C19 Inhibitors (Moderate) may increase the serum concentration of Citalopram. Management: Limit citalopram dose to a maximum of 20 mg/day if used with a moderate CYP2C19 inhibitor. Patients using this combination should be monitored closely for evidence of citalopram toxicity (e.g., serotonin syndrome, QT prolongation, etc.). Consider therapy modification

Clopidogrel: CYP2C19 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to a risk for impaired clopidogrel effectiveness with such a combination, carefully consider the need for a moderate CYP2C19 inhibitor in patients receiving clopidogrel. Monitor patients closely for evidence of a diminished response to clopidogrel. Consider therapy modification

CloZAPine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of CloZAPine. Monitor therapy

Cobicistat: Ketoconazole (Systemic) may increase the serum concentration of Cobicistat. Cobicistat may increase the serum concentration of Ketoconazole (Systemic). Management: Limit ketoconazole to a maximum adult dose of 200 mg/day in patients being treated with the elvitegravir/cobicistat/emtricitabine/tenofovir combination product. Dosing recommendations for other cobicistat-containing products are not available. Consider therapy modification

Cobimetinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Cobimetinib. Avoid combination

Colchicine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Colchicine. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a strong CYP3A4 inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. Consider therapy modification

Conivaptan: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Conivaptan. Fluconazole and isavuconazonium considerations are addressed in separate monographs. Avoid combination

Conivaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Conivaptan. Avoid combination

Corticosteroids (Orally Inhaled): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Corticosteroids (Orally Inhaled). Management: Orally inhaled fluticasone propionate with a strong CYP3A4 inhibitor is not recommended. Exceptions: Beclomethasone (Oral Inhalation); Triamcinolone (Systemic). Monitor therapy

Corticosteroids (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Corticosteroids (Systemic). Exceptions: MethylPREDNISolone; PrednisoLONE (Systemic); PredniSONE. Monitor therapy

Crizotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Crizotinib. Avoid combination

CycloSPORINE (Systemic): Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of CycloSPORINE (Systemic). Fluconazole and isavuconazonium considerations are addressed in separate monographs. Consider therapy modification

CYP2A6 Substrates: CYP2A6 Inhibitors (Moderate) may decrease the metabolism of CYP2A6 Substrates. Monitor therapy

CYP2C19 Substrates: CYP2C19 Inhibitors (Moderate) may decrease the metabolism of CYP2C19 Substrates. Monitor therapy

CYP2C9 Substrates: CYP2C9 Inhibitors (Moderate) may decrease the metabolism of CYP2C9 Substrates. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Substrates: CYP3A4 Inhibitors (Strong) may decrease the metabolism of CYP3A4 Substrates. Exceptions: Alitretinoin (Systemic); AmLODIPine; Buprenorphine; Gefitinib; HYDROcodone; Praziquantel; Telithromycin; Vinorelbine. Consider therapy modification

Dabigatran Etexilate: Ketoconazole (Systemic) may increase the serum concentration of Dabigatran Etexilate. Management: Dose reductions and/or avoidance of this combination may be necessary. Specific recommendations vary by U.S. vs. Canadian labeling, renal function, and indication for dabigatran. Refer to full monograph or dabigatran labeling. Consider therapy modification

Dabrafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dabrafenib. Avoid combination

Daclatasvir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Daclatasvir. Management: Decrease the daclatasvir dose to 30 mg once daily if combined with a strong CYP3A4 inhibitor. No dose adjustment is needed when daclatasvir is used with darunavir/cobicistat. Consider therapy modification

Dapoxetine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dapoxetine. Avoid combination

Darunavir: May increase the serum concentration of Ketoconazole (Systemic). Ketoconazole (Systemic) may increase the serum concentration of Darunavir. Management: Limit the adult maximum ketoconazole dose to 200 mg/day in patients receiving darunavir/ritonavir. Consider therapy modification

Dasatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dasatinib. Management: Use of this combination should be avoided; consider reducing dasatinib dose if a strong CYP3A4 inhibitor must be used. If using dasatinib 100 mg/day, consider reduction to 20 mg/day; if using dasatinib 140 mg/day, consider reduction to 40 mg/day. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Didanosine: May decrease the absorption of Antifungal Agents (Azole Derivatives, Systemic). Enteric coated didanosine capsules are not expected to affect these antifungals. Consider therapy modification

Dienogest: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dienogest. Monitor therapy

Dihydroergotamine: Ketoconazole (Systemic) may increase the serum concentration of Dihydroergotamine. Avoid combination

Disopyramide: Ketoconazole (Systemic) may increase the serum concentration of Disopyramide. Avoid combination

DOCEtaxel: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of DOCEtaxel. Fluconazole and isavuconazonium considerations are addressed in separate monographs. Consider therapy modification

Dofetilide: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Dofetilide. Avoid combination

Domperidone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Domperidone. Avoid combination

Doxercalciferol: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Doxercalciferol. Monitor therapy

DOXOrubicin (Conventional): CYP3A4 Inhibitors (Strong) may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to strong CYP3A4 inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Dronabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Dronabinol. Monitor therapy

Dronabinol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronabinol. Monitor therapy

Dronedarone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dronedarone. Avoid combination

Drospirenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Drospirenone. Monitor therapy

Dutasteride: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Dutasteride. Monitor therapy

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Efavirenz: May decrease the serum concentration of Ketoconazole (Systemic). Avoid combination

Elbasvir: Ketoconazole (Systemic) may increase the serum concentration of Elbasvir. Avoid combination

Eletriptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eletriptan. Avoid combination

Eliglustat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eliglustat. Management: Use should be avoided under some circumstances. See full drug interaction monograph for details. Consider therapy modification

Elvitegravir: Ketoconazole (Systemic) may increase the serum concentration of Elvitegravir. Management: Limit ketoconazole to a maximum dose of 200 mg/day in patients who are being treated with an elvitegravir-containing product. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Eplerenone: Ketoconazole (Systemic) may increase the serum concentration of Eplerenone. Avoid combination

Ergoloid Mesylates: Ketoconazole (Systemic) may increase the serum concentration of Ergoloid Mesylates. Avoid combination

Ergonovine: Ketoconazole (Systemic) may increase the serum concentration of Ergonovine. Avoid combination

Ergotamine: Ketoconazole (Systemic) may increase the serum concentration of Ergotamine. Avoid combination

Erlotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Erlotinib. Management: Avoid use of this combination when possible. When the combination must be used, monitor the patient closely for the development of severe adverse reactions, and if such severe reactions occur, reduce the erlotinib dose (in 50 mg decrements). Consider therapy modification

Estazolam: Ketoconazole (Systemic) may increase the serum concentration of Estazolam. Avoid combination

Eszopiclone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Eszopiclone. Management: Limit the eszopiclone dose to 2 mg daily when combined with strong CYP3A4 inhibitors and monitor for increased eszopiclone effects and toxicities (eg, somnolence, drowsiness, CNS depression). Consider therapy modification

Etizolam: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Etizolam. Management: Consider use of lower etizolam doses when using this combination; specific recommendations concerning dose adjustment are not available. Monitor clinical response to the combination closely. Consider therapy modification

Etravirine: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Etravirine. Applicable Isavuconazonium considerations are addressed in separate monographs. Etravirine may decrease the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). This would be anticipated with itraconazole or ketoconazole. Etravirine may increase the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). This would be anticipated with voriconazole. Management: Monitor for increased effects/toxicity of etravirine. Antifungal dose adjustment may be needed for ketoconazole, itraconazole, or posaconazole but specific dosing guidelines are lacking. Consider therapy modification

Everolimus: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Everolimus. Avoid combination

Felodipine: Ketoconazole (Systemic) may increase the serum concentration of Felodipine. Avoid combination

FentaNYL: CYP3A4 Inhibitors (Strong) may increase the serum concentration of FentaNYL. Management: Monitor patients closely for several days following initiation of this combination, and adjust fentanyl dose as necessary. Consider therapy modification

Fesoterodine: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fesoterodine. Management: Avoid fesoterodine doses greater than 4 mg daily in adult patients who are also receiving strong CYP3A4 inhibitors. Consider therapy modification

Fexofenadine: Ketoconazole (Systemic) may increase the serum concentration of Fexofenadine. Monitor therapy

Fimasartan: Ketoconazole (Systemic) may increase the serum concentration of Fimasartan. Monitor therapy

Fingolimod: Ketoconazole (Systemic) may increase serum concentrations of the active metabolite(s) of Fingolimod. Ketoconazole (Systemic) may increase the serum concentration of Fingolimod. Monitor therapy

Flibanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Flibanserin. Avoid combination

Fluticasone (Nasal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Nasal). Monitor therapy

Fluticasone (Oral Inhalation): CYP3A4 Inhibitors (Strong) may increase the serum concentration of Fluticasone (Oral Inhalation). Management: Use of orally inhaled fluticasone propionate with strong CYP3A4 inhibitors is not recommended. Use of orally inhaled fluticasone furoate with strong CYP3A4 inhibitors should be done with caution. Monitor patients using such a combination more closely. Consider therapy modification

Fosamprenavir: Ketoconazole (Systemic) may increase serum concentrations of the active metabolite(s) of Fosamprenavir. Specifically, amprenavir concentrations may be increased. Fosamprenavir may increase the serum concentration of Ketoconazole (Systemic). Management: Limit the adult maximum ketoconazole dose to 200 mg/day with fosamprenavir/ritonavir. In patients receiving fosamprenavir without ritonavir, patients receiving greater than 400 mg/day ketoconazole may also require dose reduction. Consider therapy modification

Fosphenytoin: May decrease the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Fosphenytoin. Applicable Isavuconazonium considerations are addressed in separate monographs. Consider therapy modification

Gefitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Gefitinib. Monitor therapy

Grazoprevir: Ketoconazole (Systemic) may increase the serum concentration of Grazoprevir. Avoid combination

GuanFACINE: CYP3A4 Inhibitors (Strong) may increase the serum concentration of GuanFACINE. Management: Reduce the guanfacine dose by 50% when initiating this combination. Consider therapy modification

H2-Antagonists: May decrease the serum concentration of Ketoconazole (Systemic). Management: Administer oral ketoconazole at least 2 hours prior to use of any H2-receptor antagonist. Monitor patients closely for signs of inadequate clinical response to ketoconazole. Consider therapy modification

Halofantrine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Halofantrine. Avoid combination

Highest Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

HYDROcodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of HYDROcodone. Monitor therapy

Ibrutinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ibrutinib. Management: If a strong CYP3A inhibitor must be used short-term (e.g. antifungals and antibiotics for 7 days or less), consider stopping ibrutinib until the CYP3A inhibitor is no longer needed. Avoid combination

Idelalisib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Idelalisib. Monitor therapy

Ifosfamide: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ifosfamide. Monitor therapy

Iloperidone: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolites P88 and P95 may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Iloperidone. Management: Reduce iloperidone dose by half when administered with a strong CYP3A4 inhibitor. Consider therapy modification

Imatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imatinib. Monitor therapy

Imidafenacin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Imidafenacin. Monitor therapy

Indinavir: Ketoconazole (Systemic) may increase the serum concentration of Indinavir. Indinavir may increase the serum concentration of Ketoconazole (Systemic). Management: Reduce the normal indinavir adult dose to 600 mg every 8 hours when given with ketoconazole. Monitor for increased systemic effects (including adverse/toxic effects) of ketoconazole. Consider therapy modification

Indium 111 Capromab Pendetide: Antiandrogens may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Avoid combination

Irinotecan Products: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, serum concentrations of SN-38 may be increased. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Irinotecan Products. Avoid combination

Irinotecan Products: UGT1A1 Inhibitors may increase serum concentrations of the active metabolite(s) of Irinotecan Products. Specifically, concentrations of SN-38 may be increased. UGT1A1 Inhibitors may increase the serum concentration of Irinotecan Products. Avoid combination

Isavuconazonium Sulfate: CYP3A4 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Isavuconazonium Sulfate. Specifically, CYP3A4 Inhibitors (Strong) may increase isavuconazole serum concentrations. Management: Combined use is considered contraindicated per US labeling. Lopinavir/ritonavir (and possibly other uses of ritonavir doses less than 400 mg every 12 hours) is treated as a possible exception to this contraindication despite strongly inhibiting CYP3A4. Avoid combination

Isoniazid: May decrease the serum concentration of Ketoconazole (Systemic). Monitor therapy

Ivabradine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivabradine. Avoid combination

Ivacaftor: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult prescribing information for specific age- and weight-based recommendations. Consider therapy modification

Ixabepilone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ixabepilone. Consider therapy modification

Lacosamide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lacosamide. Monitor therapy

Lapatinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lapatinib. Management: If an overlap in therapy cannot be avoided, consider reducing lapatinib adult dose to 500 mg/day during, and within 1 week of completing, treatment with the strong CYP3A4 inhibitor. Avoid combination

Lercanidipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lercanidipine. Avoid combination

Levobupivacaine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levobupivacaine. Monitor therapy

Levomilnacipran: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Levomilnacipran. Management: Do not exceed a maximum adult levomilnacipran dose of 80 mg/day in patients also receiving strong CYP3A4 inhibitors. Consider therapy modification

Lomitapide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lomitapide. Avoid combination

Lopinavir: Ketoconazole (Systemic) may increase the serum concentration of Lopinavir. Lopinavir may increase the serum concentration of Ketoconazole (Systemic). Management: Limit the adult maximum ketoconazole dose to 200 mg/day in patients receiving lopinavir/ritonavir. Consider therapy modification

Losartan: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Losartan. Applicable Isavuconazonium considerations are addressed in separate monographs. Monitor therapy

Lovastatin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lovastatin. Avoid combination

Lumacaftor: May decrease the serum concentration of Ketoconazole (Systemic). Avoid combination

Lurasidone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Lurasidone. Avoid combination

Macitentan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Macitentan. Avoid combination

Maraviroc: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Maraviroc. Management: Reduce the adult dose of maraviroc to 150 mg twice daily when used with a strong CYP3A4 inhibitor. Do not use maraviroc with strong CYP3A4 inhibitors in patients with Clcr less than 30 mL/min. Consider therapy modification

MedroxyPROGESTERone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MedroxyPROGESTERone. Monitor therapy

Methadone: Ketoconazole (Systemic) may increase the serum concentration of Methadone. Avoid combination

Methylergonovine: Ketoconazole (Systemic) may increase the serum concentration of Methylergonovine. Avoid combination

MethylPREDNISolone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MethylPREDNISolone. Management: Consider methylprednisolone dose reduction in patients receiving strong CYP3A4 inhibitors and monitor for increased steroid related adverse effects. Consider therapy modification

Midazolam: Ketoconazole (Systemic) may increase the serum concentration of Midazolam. Avoid combination

MiFEPRIStone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of MiFEPRIStone. Management: Limit mifepristone adult dose, when used for treatment of hyperglycemia in Cushing's syndrome, to a maximum of 300 mg/day when combined with a strong CYP3A4 inhibitor. Monitor for increased mifepristone toxicity regardless of dose or indication. Consider therapy modification

MiFEPRIStone: May enhance the QTc-prolonging effect of QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying). Management: Though the drugs listed here have uncertain QT-prolonging effects, they all have some possible association with QT prolongation and should generally be avoided when possible. Consider therapy modification

Mirabegron: Ketoconazole (Systemic) may increase the serum concentration of Mirabegron. Monitor therapy

Mirodenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Mirodenafil. Management: Consider using a lower dose of mirodenafil when used with strong CYP3A4 inhibitors. Monitor for increased mirodenafil effects/toxicities with the use of this combination. Consider therapy modification

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Moderate Risk QTc-Prolonging Agents: QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying) may enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Naloxegol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Naloxegol. Avoid combination

Nevirapine: May decrease the serum concentration of Ketoconazole (Systemic). Avoid combination

Nilotinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nilotinib. Avoid combination

NiMODipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of NiMODipine. Avoid combination

Nintedanib: Combined Inhibitors of CYP3A4 and P-glycoprotein may increase the serum concentration of Nintedanib. Monitor therapy

Nisoldipine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Nisoldipine. Avoid combination

Olaparib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Olaparib. Management: Avoid use of strong CYP3A4 inhibitors in patients being treated with olaparib. If such concurrent use cannot be avoided, the dose of olaparib should be reduced to 150 mg twice daily. Avoid combination

Ospemifene: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ospemifene. Monitor therapy

Oxybutynin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Oxybutynin. Monitor therapy

OxyCODONE: CYP3A4 Inhibitors (Strong) may enhance the adverse/toxic effect of OxyCODONE. CYP3A4 Inhibitors (Strong) may increase the serum concentration of OxyCODONE. Serum concentrations of the active metabolite oxymorphone may also be increased. Consider therapy modification

Palbociclib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Palbociclib. Avoid combination

Panobinostat: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Panobinostat. Management: Reduce the panobinostat dose to 10 mg when it must be used with a strong CYP3A4 inhibitor. Consider therapy modification

Parecoxib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Parecoxib. Monitor therapy

Paricalcitol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Paricalcitol. Monitor therapy

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Monitor therapy

Phenytoin: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Phenytoin. Applicable Isavuconazonium considerations are addressed in separate monographs. Phenytoin may decrease the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). Management: Concomitant therapy with itraconazole, voriconazole, or ketoconazole and phenytoin should probably be avoided, as antifungal failure is likely. Consider selecting alternative antifungal therapy. Consider therapy modification

Pimavanserin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pimavanserin. Consider therapy modification

Pimecrolimus: CYP3A4 Inhibitors (Strong) may decrease the metabolism of Pimecrolimus. Monitor therapy

Pimozide: Antifungal Agents (Azole Derivatives, Systemic) may enhance the arrhythmogenic effect of Pimozide. Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Pimozide. This increase in serum concentrations may lead to QTc interval prolongation and ventricular arrhythmias. Applicable Isavuconazonium considerations are addressed in separate monographs. Avoid combination

Pimozide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pimozide. Avoid combination

PONATinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of PONATinib. Management: Per ponatinib U.S. prescribing information, the adult starting dose of ponatinib should be reduced to 30 mg daily during treatment with any strong CYP3A4 inhibitor. Consider therapy modification

Pranlukast: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Pranlukast. Monitor therapy

Prasugrel: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Prasugrel. Monitor therapy

Praziquantel: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Praziquantel. Monitor therapy

PrednisoLONE (Systemic): CYP3A4 Inhibitors (Strong) may increase the serum concentration of PrednisoLONE (Systemic). Monitor therapy

PredniSONE: CYP3A4 Inhibitors (Strong) may increase the serum concentration of PredniSONE. Monitor therapy

Propafenone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Propafenone. Monitor therapy

Proton Pump Inhibitors: May decrease the serum concentration of Ketoconazole (Systemic). Ketoconazole (Systemic) may increase the serum concentration of Proton Pump Inhibitors. Consider therapy modification

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

QUEtiapine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of QUEtiapine. Management: In quetiapine treated patients, reduce the quetiapine dose to one sixth of the regular dose following strong CYP3A4 inhibitor initiation. In patients receiving strong CYP3A4 inhibitors, initiate quetiapine at the lowest dose and up-titrate as needed. Consider therapy modification

QuiNIDine: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of QuiNIDine. Applicable Isavuconazonium considerations are addressed in separate monographs. Avoid combination

Ramelteon: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ramelteon. Monitor therapy

Ranolazine: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Ranolazine. Fluconazole and isavuconazonium considerations are addressed in separate monographs. Avoid combination

Ranolazine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ranolazine. Avoid combination

Reboxetine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Reboxetine. Consider therapy modification

Red Yeast Rice: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Red Yeast Rice. Specifically, concentrations of lovastatin and related compounds found in Red Yeast Rice may be increased. Avoid combination

Regorafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Regorafenib. Avoid combination

Repaglinide: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Repaglinide. Management: The addition of a CYP2C8 inhibitor to this drug combination may substantially increase the magnitude of increase in repaglinide exposure. Monitor therapy

Retapamulin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Retapamulin. Management: Avoid this combination in patients less than 2 years old. No action is required in other populations. Monitor therapy

Rifamycin Derivatives: Antifungal Agents (Azole Derivatives, Systemic) may increase the serum concentration of Rifamycin Derivatives. Only rifabutin appears to be affected. Rifamycin Derivatives may decrease the serum concentration of Antifungal Agents (Azole Derivatives, Systemic). Management: Avoid these combinations when possible. Voriconazole and isavuconazonium are considered contraindicated. Consider therapy modification

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy

Rilpivirine: Ketoconazole (Systemic) may increase the serum concentration of Rilpivirine. Rilpivirine may decrease the serum concentration of Ketoconazole (Systemic). Monitor therapy

Riociguat: Ketoconazole (Systemic) may increase the serum concentration of Riociguat. Management: Consider starting with a reduced riociguat dose of 0.5 mg three times a day. Patients receiving such a combination should also be monitored extra closely for signs or symptoms of hypotension. Consider therapy modification

Ritonavir: May increase the serum concentration of Ketoconazole (Systemic). Management: Limit the adult maximum ketoconazole dose to 200 mg/day in patients receiving ritonavir. Consider therapy modification

Rivaroxaban: Inhibitors of CYP3A4 (Strong) and P-glycoprotein may increase the serum concentration of Rivaroxaban. Avoid combination

RomiDEPsin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of RomiDEPsin. Monitor therapy

Ruxolitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ruxolitinib. Management: This combination should be avoided under some circumstances. See monograph for details. Consider therapy modification

Saccharomyces boulardii: Antifungal Agents (Systemic, Oral) may diminish the therapeutic effect of Saccharomyces boulardii. Avoid combination

Salmeterol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Salmeterol. Avoid combination

Saquinavir: May increase the serum concentration of Ketoconazole (Systemic). Ketoconazole (Systemic) may increase the serum concentration of Saquinavir. Management: Limit the adult maximum ketoconazole dose to 200 mg/day in patients receiving saquinavir/ritonavir. Consider therapy modification

SAXagliptin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of SAXagliptin. Management: Saxagliptin U.S. product labeling recommends limiting saxagliptin adult dose to 2.5 mg/day when used with a strong CYP3A4 inhibitor. Monitor for increased saxagliptin levels/effects. A similar recommendation is not made in the Canadian product labeling. Consider therapy modification

Sildenafil: Ketoconazole (Systemic) may increase the serum concentration of Sildenafil. Management: Concurrent ketoconazole is not recommended when sildenafil is used for treatment of pulmonary arterial hypertension. If sildenafil is used to treat erectile dysfunction, an initial dose of 25 mg is recommended with concurrent ketoconazole. Consider therapy modification

Silodosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Silodosin. Avoid combination

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Avoid combination

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simeprevir. Avoid combination

Simvastatin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Simvastatin. Avoid combination

Sirolimus: Ketoconazole (Systemic) may increase the serum concentration of Sirolimus. Management: Sirolimus dose adjustments will likely be needed when starting/stopping any azole antifungal. Clinical data suggest sirolimus (adult) dose reductions of 50-90% will be needed when starting an azole antifungal, but specific guidelines are lacking. Consider therapy modification

Solifenacin: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Solifenacin. Applicable Isavuconazonium considerations are addressed in separate monographs. Consider therapy modification

Sonidegib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Sonidegib. Avoid combination

SORAfenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of SORAfenib. Monitor therapy

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Sucralfate: May decrease the serum concentration of Ketoconazole (Systemic). Monitor therapy

SUNItinib: Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of SUNItinib. Applicable Isavuconazonium considerations are addressed in separate monographs. Consider therapy modification

Suvorexant: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Suvorexant. Avoid combination

Tacrolimus (Systemic): Ketoconazole (Systemic) may increase the serum concentration of Tacrolimus (Systemic). Management: Tacrolimus dose adjustment may be required when taken with ketoconazole due to elevated plasma concentrations of tacrolimus. Monitor tacrolimus concentrations and clinical response closely. Consider therapy modification

Tacrolimus (Topical): Antifungal Agents (Azole Derivatives, Systemic) may decrease the metabolism of Tacrolimus (Topical). Applicable Isavuconazonium considerations are addressed in separate monographs. Monitor therapy

Tadalafil: Ketoconazole (Systemic) may increase the serum concentration of Tadalafil. Consider therapy modification

Tamsulosin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tamsulosin. Avoid combination

Tasimelteon: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tasimelteon. Monitor therapy

Tegafur: CYP2A6 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Tegafur. Specifically, CYP2A6 inhibitors may inhibit the conversion of tegafur into its active metabolite, 5-fluorouracil. Avoid combination

Telaprevir: Ketoconazole (Systemic) may increase the serum concentration of Telaprevir. Telaprevir may increase the serum concentration of Ketoconazole (Systemic). Management: Doses of ketoconazole greater than 200 mg/day are not recommended in patients receiving telaprevir. Use extra caution when using these drugs in combination. Consider therapy modification

Telithromycin: Ketoconazole (Systemic) may increase the serum concentration of Telithromycin. Telithromycin may increase the serum concentration of Ketoconazole (Systemic). Avoid combination

Temsirolimus: Ketoconazole (Systemic) may increase serum concentrations of the active metabolite(s) of Temsirolimus. Management: Temsirolimus dose adjustments will likely be needed when starting/stopping/changing ketoconazole. Clinical data suggest temsirolimus (adult) dose reductions of around 50% should be considered, but specific guidelines are lacking. Consider therapy modification

Terfenadine: Ketoconazole (Systemic) may enhance the QTc-prolonging effect of Terfenadine. Ketoconazole (Systemic) may increase the serum concentration of Terfenadine. Avoid combination

Tetrahydrocannabinol: CYP2C9 Inhibitors (Moderate) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Tetrahydrocannabinol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tetrahydrocannabinol. Monitor therapy

Ticagrelor: CYP3A4 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Ticagrelor. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ticagrelor. Avoid combination

Tipranavir: May increase the serum concentration of Ketoconazole (Systemic). Management: Limit ketoconazole adult maximum dose to 200 mg/day in patients treated with tipranavir. Consider therapy modification

TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use cannot be avoided, initiate tizanidine at an adult dose of 2 mg and increase in 2-4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Tofacitinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tofacitinib. Management: Reduce the adult dose of tofacitinib to 5 mg daily in patients receiving strong CYP3A4 inhibitors. Consider therapy modification

Tolterodine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolterodine. Management: The maximum recommended adult dose of tolterodine is 2 mg/day when used together with a strong CYP3A4 inhibitor. Consider therapy modification

Tolvaptan: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Tolvaptan. Avoid combination

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Toremifene: CYP3A4 Inhibitors (Strong) may enhance the adverse/toxic effect of Toremifene. CYP3A4 Inhibitors (Strong) may increase the serum concentration of Toremifene. Avoid combination

Trabectedin: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Trabectedin. Avoid combination

TraMADol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of TraMADol. Monitor therapy

Triazolam: Ketoconazole (Systemic) may increase the serum concentration of Triazolam. Avoid combination

Udenafil: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Udenafil. Avoid combination

Ulipristal: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Ulipristal. Management: This is specific for when ulipristal is being used for signs/symptoms of uterine fibroids (Canadian indication). When ulipristal is used as an emergency contraceptive, patients receiving this combo should be monitored for ulipristal toxicity. Avoid combination

Vardenafil: Ketoconazole (Systemic) may increase the serum concentration of Vardenafil. Management: Limit vardenafil dosing to a maximum of 5 mg per 24 hours in patients receiving ketoconazole 200 mg/day, and a maximum of 2.5 mg per 24 hours in patients receiving ketoconazole 400 mg/day. Consider therapy modification

Vemurafenib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vemurafenib. Avoid combination

Venetoclax: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Venetoclax. Management: These combinations are contraindicated during venetoclax initiation and ramp-up. In patients receiving steady venetoclax doses after completing ramp-up, reduce the venetoclax by at least 75% if strong CYP3A4 inhibitor use cannot be avoided. Consider therapy modification

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

Vilazodone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vilazodone. Management: Limit maximum adult vilazodone dose to 20 mg/day in patients receiving strong CYP3A4 inhibitors. The original vilazodone dose can be resumed following discontinuation of the strong CYP3A4 inhibitor. Consider therapy modification

VinCRIStine (Liposomal): CYP3A4 Inhibitors (Strong) may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Vindesine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vindesine. Monitor therapy

Vinflunine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vinflunine. Avoid combination

Vinorelbine: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vinorelbine. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Ketoconazole (Systemic) may increase the serum concentration of Vitamin K Antagonists. Monitor therapy

Vorapaxar: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Vorapaxar. Avoid combination

Zolpidem: Ketoconazole (Systemic) may increase the serum concentration of Zolpidem. Management: Consider using a lower starting dose of zolpidem in patients receiving ketoconazole and monitor for increased zolpidem effects/toxicities if these agents are combined. Consider therapy modification

Zopiclone: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zopiclone. Management: The initial starting adult dose of zopiclone should not exceed 3.75 mg if combined with a strong CYP3A4 inhibitor. Monitor patients for signs and symptoms of zopiclone toxicity if these agents are combined. Consider therapy modification

Zuclopenthixol: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Zuclopenthixol. Management: Consider zuclopenthixol dosage reduction with concomitant use of a strong CYP3A4 inhibitor (eg, ketoconazole) in poor CYP2D6 metabolizers or with strong CYP2D6 inhibitors (eg, paroxetine). Monitor for increased zuclopenthixol levels/toxicity. Consider therapy modification

Adverse Reactions

Frequency not always defined.

Cardiovascular: Orthostatic hypotension, peripheral edema

Central nervous system: Fatigue, insomnia, malaise, nervousness, paresthesia

Dermatologic: Pruritus (2%), alopecia, dermatitis, erythema, erythema multiforme, skin rash, urticaria, xeroderma

Endocrine & metabolic: Hot flash, hyperlipidemia, menstrual disease

Gastrointestinal: Nausea (3%), vomiting (3%), abdominal pain (1%), anorexia, constipation, dysgeusia, dyspepsia, flatulence, increased appetite, tongue discoloration, upper abdominal pain, xerostomia

Hematologic & oncologic: Decreased platelet count

Hepatic: Jaundice

Hypersensitivity: Anaphylactoid reaction

Neuromuscular & skeletal: Myalgia, weakness

Respiratory: Epistaxis

Miscellaneous: Alcohol intolerance

<1% (Limited to important or life-threatening): Acute generalized exanthematous pustulosis, adrenocortical insufficiency (≥400 mg/day), anaphylactic shock, anaphylaxis, angioedema, azoospermia, bulging fontanel (infants), cholestatic hepatitis, cirrhosis, decreased plasma testosterone (impaired at 800 mg/day), depression, erectile dysfunction (doses >200-400 mg/day), gynecomastia, hemolytic anemia, hepatic failure, hepatic necrosis, hepatitis, hepatotoxicity, hypertriglyceridemia, hypersensitivity reaction, impotence, increased intracranial pressure (reversible), leukopenia, myopathy, papilledema, photophobia, prolonged Q-T interval on ECG, skin photosensitivity, suicidal tendencies, thrombocytopenia

ALERT: U.S. Boxed Warning

Appropriate use:

Use ketoconazole only when other effective antifungal therapy is not available or tolerated and the potential benefits are considered to outweigh the potential risks.

Hepatotoxicity:

Serious hepatotoxicity, including cases with a fatal outcome or requiring liver transplantation, has occurred with the use of ketoconazole. Some patients had no obvious risk factors for liver disease. Inform patients receiving this drug of the risk and closely monitor.

QT prolongation and drug interactions leading to QT prolongation:

Coadministration of the following drugs with ketoconazole is contraindicated: dofetilide, quinidine, pimozide, cisapride, methadone, disopyramide, dronedarone, and ranolazine. Ketoconazole can cause elevated plasma concentrations of these drugs and may prolong QT intervals, sometimes resulting in life-threatening ventricular dysrhythmias, such as torsades de pointes.

Warnings/Precautions

Concerns related to adverse effects:

• Adrenal suppression: High doses of ketoconazole may depress adrenocortical function; returns to baseline upon discontinuation of therapy. Recommended maximum dosing should not be exceeded. Monitor adrenal function as clinically necessary, particularly in patients with adrenal insufficiency and in patients under prolonged stress (eg, intensive care, major surgery).

• Bone fragility: In animal studies, increased long bone fragility with cases of fracture has been observed with high-dose ketoconazole. Careful dose selection may be advisable for patients susceptible to bone fragility (eg, postmenopausal women, elderly).

• Hypersensitivity reactions: Cases of hypersensitivity reactions (including rare cases of anaphylaxis) have been reported; some reactions occurred after the initial dose.

• Myopathy: Coadministration with HMG-CoA reductase inhibitors (eg, lovastatin, simvastatin) may increase the risk of myopathy. Concomitant use is contraindicated.

• Sedation: Coadministration with midazolam, triazolam, and alprazolam may result in elevated plasma concentrations of the benzodiazepines, leading to prolonged hypnotic and sedative effects. Concomitant use is contraindicated.

Disease-related concerns:

• Achlorhydria: Absorption is reduced in patients with achlorhydria; administer with acidic liquids (eg, soda pop). Avoid concomitant use of drugs that decrease gastric acidity (eg, proton pump inhibitors, antacids, H2-blockers).

• CNS infections: Ketoconazole has poor penetration into cerebral-spinal fluid and should not be used to treat fungal meningitis.

• Hepatic impairment: [US Boxed Warning]: Ketoconazole has been associated with hepatotoxicity, including fatal cases and cases requiring liver transplantation; some patients had no apparent risk factors for hepatic disease. Patients should be advised of the hepatotoxicity risks and monitored closely. Toxicity was observed after a median duration of therapy of ~4 weeks, but has also been noted after as little as 3 days; may occur when patients receive high doses for short durations or low doses for long durations. Most cases have been observed in the treatment of onychomycosis. Use with caution in patients with preexisting hepatic impairment, those on prolonged therapy and/or taking other hepatotoxic drugs concurrently. Hepatic dysfunction is typically (but not always) reversible upon discontinuation. Obtain liver function tests at baseline and frequently throughout therapy; serum ALT should be monitored weekly throughout therapy. Discontinue therapy for elevated hepatic enzymes that persist or worsen or if accompanied by signs/symptoms (eg, jaundice, nausea/vomiting, dark urine) of hepatic injury.

• Prostate cancer: In European clinical trials of men with metastatic prostate cancer, fatalities were reported in a small number of study participants within 14 days of initiating high-dose ketoconazole (1,200 mg daily); a causal effect has not been established.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• QT prolongation: [US Boxed Warning]: Concomitant use with cisapride, disopyramide, dofetilide, dronedarone, methadone, pimozide, quinidine, and ranolazine is contraindicated due to the possible occurrence of life-threatening ventricular arrhythmias such as torsade de pointes.

Other warnings/precautions:

• Appropriate use: [US Boxed Warning]: Use only when other effective antifungal therapy is unavailable or not tolerated and the benefits of ketoconazole treatment are considered to outweigh the risks. Ketoconazole oral tablets are approved to treat systemic fungal infections and should not be prescribed to treat skin and nail fungal infections. The risks of serious liver damage, adrenal gland problems and drug-drug interactions outweigh any potential benefit.

Monitoring Parameters

Hepatic function tests (baseline and frequently during therapy), including weekly ALT for the duration of treatment; Canadian labeling recommends monitoring hepatic function at baseline, at weeks 2 and 4, and monthly thereafter; calcium and phosphorous (periodically with long-term use); adrenal function as clinically necessary

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse effects were noted in animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience abdominal pain, nausea, diarrhea, or headache. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of adrenal gland problems (severe nausea, vomiting, severe dizziness, passing out, muscle weakness, severe fatigue, mood changes, lack of appetite, or weight loss), tachycardia, abnormal heartbeat, sensitivity to bright lights, enlarged breasts, burning or numbness feeling, swelling of arms or legs, bruising, bleeding, dizziness, angina, or passing out (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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