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Posaconazole

Pronunciation

(poe sa KON a zole)

Index Terms

  • SCH 56592

Dosage Forms

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

Solution, Intravenous:

Noxafil: 300 mg/16.7 mL (16.7 mL) [contains edetate disodium]

Suspension, Oral:

Noxafil: 40 mg/mL (105 mL) [contains polysorbate 80, sodium benzoate; cherry flavor]

Tablet Delayed Release, Oral:

Noxafil: 100 mg

Brand Names: U.S.

  • Noxafil

Pharmacologic Category

  • Antifungal Agent, Oral

Pharmacology

Interferes with fungal cytochrome P450 (lanosterol-14α-demethylase) activity, decreasing ergosterol synthesis (principal sterol in fungal cell membrane) and inhibiting fungal cell membrane formation.

Absorption

Coadministration of the tablets or oral suspension with food or coadministration of the oral suspension with liquid nutritional supplements and/or acidic carbonated beverages (eg, ginger ale) increases absorption; fasting states do not provide sufficient absorption to ensure adequate plasma concentrations.

Distribution

Vd: Oral: 287 L; Injection: ~261 L

Metabolism

Not significantly metabolized; 17% undergoes non-CYP-mediated metabolism, primarily via hepatic glucuronidation into metabolites

Excretion

Feces 71% (~66% of the total dose as unchanged drug); urine 13% (<0.2% of the total dose as unchanged drug)

Time to Peak

Plasma: Suspension: ~3 to 5 hours; Tablets: ~4 to 5 hours

Half-Life Elimination

Suspension: 35 hours (range: 20 to 66 hours); Tablets: 26 to 31 hours; Injection: ~27 hours

Protein Binding

>98%; predominantly bound to albumin

Use: Labeled Indications

Prophylaxis of invasive Aspergillus and Candida infections: Suspension and delayed-release tablets (13 years and older) and injection (18 years and older): Prophylaxis of invasive Aspergillus and Candida infections in patients who are at high risk of developing these infections due to being severely immunocompromised (eg, hematopoietic stem cell transplant [HSCT] recipients with graft-versus-host disease [GVHD] or those with prolonged neutropenia secondary to chemotherapy for hematologic malignancies).

Oropharyngeal candidiasis: Suspension (13 years and older): Treatment of oropharyngeal candidiasis (including patients refractory to itraconazole and/or fluconazole)

Canadian labeling: Additional use (not in US labeling): Invasive Aspergillus infections: Suspension and delayed-release tablets (13 years and older) and injection (18 years and older): Treatment of invasive aspergillosis in patients refractory to or intolerant of itraconazole or amphotericin B

Use: Unlabeled

Salvage therapy of refractory or relapsed invasive fungal infections; mucormycosis

Contraindications

Coadministration with sirolimus, ergot alkaloids (eg, ergotamine, dihydroergotamine), HMG-CoA reductase inhibitors that are primarily metabolized through CYP3A4 (eg, atorvastatin, lovastatin, simvastatin), or CYP3A4 substrates that prolong the QT interval (eg, pimozide, quinidine); hypersensitivity to posaconazole, other azole antifungal agents, or any component of the formulation.

Canadian labeling: Additional contraindications (not in US labeling): Coadministration with terfenadine, astemizole, or cisapride (each drug is no longer marketed in Canada).

Dosing: Adult

Note: The delayed-release tablet and oral suspension are not to be used interchangeably due to dosing differences for each formulation.

Aspergillosis, invasive:

Prophylaxis:

Oral:

Suspension: 200 mg 3 times daily; duration of therapy is based on recovery from neutropenia or immunosuppression. In patients with acute myelogenous leukemia (AML) or myelodysplastic syndromes (MDS), posaconazole was initiated at the time of chemotherapy initiation (or if receiving anthracyclines, 24 hours after the last anthracycline dose) and was continued until recovery from neutropenia, until complete remission, or for up to 12 weeks, whichever occurred first (Cornely 2007). The Canadian labeling recommends initiating posaconazole in patients with AML or MDS several days before the anticipated onset of neutropenia and continuing for 7 days after the neutrophil count rises above 500/mm3. In patients with graft-versus-host disease (GVHD) receiving immunosuppressive therapy, posaconazole was continued for 112 days (Ullmann 2007), although the optimal duration in GVHD has not been fully defined (Tomblyn 2009).

Tablets (delayed release): Initial: 300 mg twice daily on day 1; Maintenance dose: 300 mg once daily on day 2 and thereafter. Duration is based on recovery from neutropenia or immunosuppression. The Canadian labeling recommends initiating posaconazole in patients with AML or MDS several days before the anticipated onset of neutropenia and continuing for 7 days after the neutrophil count rises above 500/mm3.

Missed doses: Take as soon as remembered. If it is <12 hours until the next dose, skip the missed does and return to the regular schedule. Do not double doses.

IV: Loading dose: 300 mg twice a day on day 1; maintenance dose: 300 mg once daily on day 2 and thereafter. Duration is based on recovery from neutropenia or immunosuppression. The Canadian labeling recommends initiating posaconazole in patients with AML or MDS several days before the anticipated onset of neutropenia and continuing for 7 days after the neutrophil count rises above 500/mm3.

Treatment (refractory to or intolerant of conventional therapy):

US off-label use: Oral: Suspension: 200 mg 4 times daily initially; after disease stabilization, may decrease frequency to 400 mg twice daily (Walsh 2007). Note: Duration of therapy should be a minimum of 6 to 12 weeks or throughout period of immunosuppression and until lesions have resolved (Walsh 2008). Duration of therapy in HIV-infected patients should be until infection resolution and CD4 count >200 cells/mm3 (HHS [OI adult 2015])

Canadian labeling:

Oral:

Suspension: 400 mg twice daily; in patients unable to tolerate food or nutritional supplement, administer 200 mg 4 times daily; duration of therapy is based on severity of underlying disease, recovery from immunosuppression, and clinical response.

Tablets (delayed release): Initial: 300 mg twice daily on day 1; Maintenance dose: 300 mg once daily; duration of therapy is based on disease severity, recovery from immunosuppression, and clinical response.

IV: Loading dose: 300 mg twice daily on day 1; Maintenance dose: 300 mg once daily on day 2 and thereafter. Duration of therapy is based on disease severity, recovery from immunosuppression, and clinical response.

Candidal infections:

US labeling:

Prophylaxis:

Oral:

Suspension: 200 mg 3 times daily; duration of therapy is based on recovery from neutropenia or immunosuppression

Tablets (delayed release): Oral: Initial: 300 mg twice daily on day 1; Maintenance dose: 300 mg once daily on day 2 and thereafter; duration of therapy is based on recovery from neutropenia or immunosuppression

Missed doses: Take as soon as remembered. If it is <12 hours until the next dose, skip the missed does and return to the regular schedule. Do not double doses.

IV: Initial: 300 mg twice daily on day 1; Maintenance dose: 300 mg once daily on day 2 and thereafter; duration of therapy is based on recovery from neutropenia or immunosuppression.

Treatment: Oral: Suspension:

Oropharyngeal infection: Initial: 100 mg twice daily on day 1; Maintenance: 100 mg once daily on day 2 and thereafter for 13 days

Refractory oropharyngeal infection:

Manufacturer’s labeling: 400 mg twice daily; duration of therapy is based on underlying disease and clinical response

Alternate dosing: HIV-infected patients (alternative to fluconazole or azole refractory): 400 mg twice daily on day 1, then 400 mg once daily for 7 to 14 days for initial episodes (continue for 28 days in azole refractory patients) (HHS [OI adult 2015])

Esophageal infection in HIV-infected patients (azole refractory) (off-label use): 400 mg twice daily for 28 days. Note: If patient has frequent or severe recurrences, may continue for suppressive therapy; consider discontinuing when CD4 >200/mm3 (HHS [OI adult 2015])

Canadian labeling:

Prophylaxis: Note: Initiate posaconazole in patients with AML or MDS several days before the anticipated onset of neutropenia and continue therapy for 7 days after the neutrophil count rises above 500/mm3.

Oral:

Suspension: 200 mg 3 times daily; duration of therapy is based on recovery from neutropenia or immunosuppression.

Tablets (delayed release): Initial: 300 mg twice daily on day 1; Maintenance dose: 300 mg once daily on day 2 and thereafter; duration of therapy is based on recovery from neutropenia or immunosuppression.

Injection: IV: Initial: 300 mg twice daily on day 1; Maintenance dose: 300 mg once daily on day 2 and thereafter; duration of therapy is based on recovery from neutropenia or immunosuppression.

Treatment: Oral: Suspension: Oropharyngeal infection: Initial: 100 mg twice daily for 1 day; Maintenance: 100 mg once daily for 13 days

Coccidioidomycosis in HIV-infected patients (alternative to preferred therapy) (off-label use; HHS [OI adult 2015]): Oral:

Mild infections (eg, focal pneumonia): 200 to 400 mg twice daily; patients who complete initial therapy should be considered for lifelong suppressive therapy.

Chronic suppressive therapy: 200 mg twice daily

Mucormycosis (off-label use): Suspension: Oral: 800 mg daily in 2 or 4 divided doses; duration of therapy is based on response and risk of relapse due to immunosuppression (Greenberg 2006)

Cryptococcal infections:

Pulmonary, nonimmunosuppressed (off-label use): 400 mg twice daily. Note: Fluconazole is considered first-line treatment (Perfect 2010).

Salvage treatment of relapsed infection (off-label use): 400 mg twice daily (or 200 mg 4 times daily) for 10 to 12 weeks. Note: Salvage treatment should only be started after an appropriate course of an induction regimen (Perfect 2010).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: The delayed-release tablet and oral suspension are not to be used interchangeably due to dosing differences for each formulation.

Aspergillosis, invasive (prophylaxis): Oral: Adolescents ≥13 years: Refer to adult dosing.

Candidal infections: Oral: Adolescents ≥13 years: Refer to adult dosing.

Coccidioidomycosis in HIV-infected patients (alternative to preferred therapy) (off-label use): Adolescents: Oral: Refer to adult dosing.

Primary antifungal prophylaxis in allogeneic HSCT with grades 2 to 4 acute graft-versus-host-disease (GVHD) or chronic extensive GVHD (guideline recommendation): Adolescents ≥13 years: Oral: Suspension: 200 mg 3 times daily beginning with GVHD diagnosis, continue until GVHD resolves (Science 2014)

Primary antifungal prophylaxis in AML or MDS in centers with a high local incidence of mold infections (alternative to fluconazole; guideline recommendation): Adolescents ≥13 years: Oral: Suspension: 200 mg 3 times daily during chemotherapy-associated neutropenia (Science 2014)

Dosing: Renal Impairment

Delayed-release tablets and oral suspension:

eGFR 20 to 80 mL/minute/1.73 m2: No dosage adjustment necessary.

eGFR <20 mL/minute/1.73 m2: No dosage adjustment necessary; however, monitor for breakthrough fungal infections due to variability in posaconazole exposure.

Intravenous infusion:

eGFR ≥ 50 mL/minute/1.73 m2: No dosage adjustment recommended

eGFR< 50 mL/minute/1.73 m2: Avoid use unless risk/benefit has been assessed; the intravenous vehicle (cyclodextrin) may accumulate. Monitor serum creatinine levels; if increases occur, consider oral therapy.

Dosing: Hepatic Impairment

US labeling:

Preexisting mild-to-severe impairment (Child-Pugh class A, B, or C): No dosage adjustment necessary.

Hepatotoxicity during treatment: There are no dosage adjustments provided in the manufacturer’s labeling; consider discontinuing therapy.

Canadian labeling: There are no dosage adjustments provided in the manufacturer’s labeling; use with caution in severe impairment.

Reconstitution

IV: Equilibrate the refrigerated vial to room temperature. Contents of vial should be withdrawn and admixed with D5W, D5W with KCl 20 mEq, D5NS, D51/2NS, 1/2NS, or NS to achieve a concentration of 1 to 2 mg/mL. The admixed solution may be colorless to yellow. Color variations in this range do not affect potency. Admixture should be used immediately; may be stored for up to 24 hours between 2°C and 8°C (36°F and 46°F).

Administration

Suspension: Oral: Shake well before use. Administer with provided measured dosing spoon during or within 20 minutes following a full meal; patients who are unable to eat a full meal may take each dose with an oral liquid nutritional supplement; or acidic carbonated beverage (eg, ginger ale). Consider an alternative antifungal in patients unable to eat a full meal or tolerate a liquid nutritional supplement or acidic carbonated beverage and who do not have the option of taking the delayed-release tablet or injection. Dosing spoon should be rinsed clean with water after each use and before storage. The oral suspension and delayed-release tablet are not to be used interchangeably due to dosing differences for each formulation.

Tablets (delayed release): Oral: Swallow tablets whole; do not divide, crush, dissolve, or chew. The US labeling recommends to administer with food. The Canadian labeling indicates that the tablet may be administered with or without food. Use only for prophylaxis indication (preferred oral formulation for this indication because it generally provides higher plasma drug exposures than oral suspension under both fed and fasted conditions). The delayed-release tablet and oral suspension are not to be used interchangeably due to dosing differences for each formulation.

Closely monitor patients with severe diarrhea or vomiting for breakthrough fungal infections.

Injection: Infuse over 90 minutes via a central venous line. Do not administer IV push or bolus. Must be infused through an in-line filter (0.22-micron polyethersulfone [PES] or polyvinylidene difluoride [PVDF]). Infusion through a peripheral line should only be used as a one-time infusion over 30 minutes in a patient who will be receiving a central venous line for subsequent doses, or to bridge a period during which a central venous line is to be replaced or is in use for another infusion. Note: In clinical trials, multiple peripheral infusions given through the same vein resulted in infusion-site reactions.

Dietary Considerations

Tablets (delayed release): US labeling recommends taking with food. Canadian labeling indicates that the tablet may be taken with or without food.

Suspension: Give during or within 20 minutes following a full meal, liquid nutritional supplement, or an acidic carbonated beverage (eg, ginger ale).

Consider alternative antifungal therapy in patients with inadequate oral intake or severe diarrhea/vomiting; if alternative therapy is not an option, closely monitoring for breakthrough fungal infections.

Adequate posaconazole absorption from GI tract and subsequent plasma concentrations are dependent on food for efficacy. Lower average plasma concentrations have been associated with an increased risk of treatment failure.

Compatibility

Stable in NS, D5W, D5W with KCl 20 mEq, D5NS, D51/2NS or 1/2NS. Do not mix with other infusion solutions.

Storage

Suspension: Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Do not freeze. The Canadian labeling recommends to discard 4 weeks after opening.

Tablets: Store between 20°C and 25°C (68°F and 77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F).

Injection: Store at 2°C to 8°C (36°F to 46°F).

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

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

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

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

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

Antineoplastic Agents (Vinca Alkaloids): Posaconazole may enhance the adverse/toxic effect of Antineoplastic Agents (Vinca Alkaloids). Posaconazole may increase the serum concentration of Antineoplastic Agents (Vinca Alkaloids). Management: Consider vinca alkaloid dose adjustment. Specific dose adjustment guidelines are not currently available. Monitor response to vinca alkaloid therapy, including development of vinca alkaloid toxicities (e.g., gastrointestinal toxicity, neurotoxicity). Consider therapy modification

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

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

Astemizole: Posaconazole may increase the serum concentration of Astemizole. Avoid combination

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

Atazanavir: Posaconazole may increase the serum concentration of Atazanavir. Monitor therapy

AtorvaSTATin: Posaconazole may increase the serum concentration of AtorvaSTATin. Avoid combination

Avanafil: Posaconazole 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: Posaconazole may increase the serum concentration of Boceprevir. Boceprevir may increase the serum concentration of Posaconazole. Monitor therapy

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

Bosutinib: CYP3A4 Inhibitors (Strong) 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

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). Management: Consider reducing the oral budesonide dose when used together with a CYP3A4 inhibitor or temporarily stopping budesonide therapy during CYP3A4 inhibitor use. Monitor patients closely for signs/symptoms of corticosteroid excess. Consider therapy modification

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

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

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

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

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

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

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

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

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

CYP3A4 Substrates: CYP3A4 Inhibitors (Strong) may decrease the metabolism of CYP3A4 Substrates. Exceptions: Buprenorphine; Gefitinib; Hydrocodone. 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

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

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

Digoxin: Posaconazole may increase the serum concentration of Digoxin. Monitor therapy

Dihydroergotamine: Posaconazole may increase the serum concentration of Dihydroergotamine. 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

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

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

Efavirenz: May decrease the serum concentration of Posaconazole. 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

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

Eplerenone: Posaconazole may increase the serum concentration of Eplerenone. Avoid combination

Ergoloid Mesylates: Posaconazole may increase the serum concentration of Ergoloid Mesylates. Avoid combination

Ergonovine: Posaconazole may increase the serum concentration of Ergonovine. Avoid combination

Ergotamine: Posaconazole 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: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Estazolam. Monitor therapy

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

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

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: Posaconazole may increase serum concentrations of the active metabolite(s) of Fosamprenavir. Fosamprenavir may decrease the serum concentration of Posaconazole. Monitor therapy

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

GlipiZIDE: Posaconazole may enhance the hypoglycemic effect of GlipiZIDE. Posaconazole may increase the serum concentration of GlipiZIDE. Monitor therapy

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

H2-Antagonists: May decrease the serum concentration of Posaconazole. Management: Avoid concurrent use of oral suspension with H2-antagonists whenever possible. Monitor patients closely for decreased antifungal effects if this combination is used. Delayed-release posaconazole tablets may be less likely to interact. 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

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

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

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

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 Posaconazole. 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: Posaconazole may enhance the QTc-prolonging effect of Methadone. Posaconazole may increase the serum concentration of Methadone. Avoid combination

Methylergonovine: Posaconazole 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

Metoclopramide: May decrease the serum concentration of Posaconazole. Monitor therapy

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

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

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

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

Osimertinib: CYP3A4 Inhibitors (Strong) may increase the serum concentration of Osimertinib. 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: CYP3A4 Inhibitors (Strong) may increase the serum concentration of PAZOPanib. Management: Avoid concurrent use of pazopanib with strong inhibitors of CYP3A4 whenever possible. If it is not possible to avoid such a combination, reduce pazopanib adult dose to 400 mg. Further dose reductions may also be required. Consider therapy modification

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

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 Posaconazole. Consider therapy modification

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

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

Ritonavir: Posaconazole may increase the serum concentration of Ritonavir. Monitor therapy

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

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: Posaconazole may increase the serum concentration of Sildenafil. Management: Concurrent posaconazole 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 posaconazole. Consider therapy modification

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

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: Posaconazole may increase the serum concentration of Sirolimus. Avoid combination

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

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): Posaconazole may increase the serum concentration of Tacrolimus (Systemic). Management: Reduce tacrolimus dose to approximately one-third of original dose when starting posaconazole. Tacrolimus blood concentrations should be monitored closely during and at discontinuation of posaconazole. 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: Posaconazole 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

Telaprevir: May increase the serum concentration of Posaconazole. Posaconazole may increase the serum concentration of Telaprevir. Monitor therapy

Temsirolimus: Posaconazole may increase serum concentrations of the active metabolite(s) of Temsirolimus. Management: Consider temsirolimus dose reductions or alternatives to posaconazole. Monitor sirolimus concentrations in all patients receiving posaconazole or any systemic azole antifungal. Consider therapy modification

Terfenadine: Posaconazole may increase the serum concentration of Terfenadine. Avoid combination

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

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

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

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: Posaconazole may increase the serum concentration of Vardenafil. Management: Limit vardenafil dosing to a maximum of 2.5 mg per 24 hours in patients receiving concurrent therapy with strong CYP3A4 inhibitors, such as posaconazole. 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

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

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

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

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

Note: Unless otherwise specified, incidences represent adverse reactions identified with oral formulations; systemic includes oral and intravenous routes. Percentages reflect data from use in comparator trials with multiple concomitant conditions and medications; some adverse reactions may be due to underlying condition(s).

>10%:

Cardiovascular: Thrombophlebitis (intravenous via peripheral venous catheter: 60%), hypertension (systemic: 8% to 18%), peripheral edema (systemic: 12% to 16%), edema (9% to 15%), hypotension (14%), tachycardia (12%)

Central nervous system: Headache (systemic: 8% to 28%), rigors (≤20%), fatigue (systemic: 3% to 17%), insomnia (1% to 17%), chills (systemic: 10% to 16%), lower extremity edema (15%), dizziness (11%), pain (1% to 11%)

Dermatologic: Skin rash (systemic: 15% to 24%), pruritus (11%)

Endocrine & metabolic: Hypokalemia (systemic: ≤30%), hypomagnesemia (systemic: 10% to 18%), weight loss (1% to 14%), hyperglycemia (11%), dehydration (1% to 11%)

Gastrointestinal: Diarrhea (systemic: 10% to 42%), nausea (systemic: 2% to 38%), vomiting (systemic: 7% to 29%), abdominal pain (systemic: 5% to 27%), constipation (systemic: 8% to 21%), anorexia (2% to 19%), mucositis (14% to 17%), stomatitis (14%), decreased appetite (systemic: 10% to 12%), oral candidiasis (1% to 12%), upper abdominal pain (systemic: 6% to 11%)

Hematologic & oncologic: Thrombocytopenia (systemic: <5% to 29%), anemia (systemic: 2% to 25%), neutropenia (4% to 23%), febrile neutropenia (20%), petechia (systemic: 8% to 11%)

Hepatic: Increased serum ALT (<5% to 17%)

Infection: Bacteremia (18%), herpes simplex infection (3% to 15%), cytomegalovirus disease (14%)

Neuromuscular & skeletal: Musculoskeletal pain (16%), weakness (2% to 13%), arthralgia (11%)

Respiratory: Cough (systemic: 3% to 25%), dyspnea (systemic: 1% to 20%), epistaxis (systemic: 14% to 17%), pharyngitis (12%)

Miscellaneous: Fever (systemic: 6% to 45%)

1% to 10%:

Cardiovascular: Pulmonary embolism (<5%), torsades de pointes (<5%)

Central nervous system: Anxiety (9%), paresthesia (<5%)

Dermatologic: Diaphoresis (2% to 10%)

Endocrine & metabolic: Hypocalcemia (9%), adrenocortical insufficiency (<5%)

Gastrointestinal: Dyspepsia (10%)

Genitourinary: Vaginal hemorrhage (10%)

Hematologic & oncologic: Hemolytic-uremic syndrome (<5%), thrombotic thrombocytopenic purpura (<5%)

Hepatic: Hyperbilirubinemia (<5% to 10%), increased serum AST (3% to <5%), hepatic failure (<5%), hepatitis (<5%), hepatomegaly (<5%), jaundice (<5%), increased liver enzymes (<5%), increased serum alkaline phosphatase (1% to 3%)

Hypersensitivity: Hypersensitivity reaction (<5%)

Neuromuscular & skeletal: Back pain (10%)

Renal: Acute renal failure (<5%)

Respiratory: Pneumonia (3% to 10%), upper respiratory tract infection (7%)

<1% (Limited to important or life-threatening): Atrial fibrillation, cholestasis, hypersensitivity, prolonged Q-T interval on ECG, reduced ejection fraction, syncope

Warnings/Precautions

Concerns related to adverse effects:

• Azole hypersensitivity: US labeling contraindicates use in patients with hypersensitivity to other azole antifungal agents; Canadian labeling does not contraindicate use, but recommends using caution in patients with hypersensitivity to other azole antifungal agents; cross-reaction may occur, but has not been established.

• Hepatic effects: Hepatic dysfunction has occurred, ranging from mild/moderate increases of ALT, AST, alkaline phosphatase, total bilirubin, and/or clinical hepatitis to severe reactions (cholestasis, hepatic failure including death). Elevations in liver function tests have been generally reversible after posaconazole has been discontinued; some cases resolved without drug interruption. More severe reactions have been observed in patients with underlying serious medical conditions (eg, hematologic malignancy) and primarily with suspension total daily doses of 800 mg. Monitor liver function tests at baseline and periodically during therapy. If increases occur, monitor for severe hepatic injury development. Consider discontinuation of therapy in patients who develop clinical evidence of liver disease that may be secondary to posaconazole.

Disease-related concerns:

• Arrhythmias: Use caution in patients with an increased risk of arrhythmia (long QT syndrome, concurrent QTc-prolonging drugs metabolized through CYP3A4, hypokalemia). Development of QTc prolongation, including torsade de pointes, has been reported. Correct electrolyte abnormalities (eg, potassium, magnesium, and calcium) before initiating therapy.

• Renal impairment: Do not use injection in patients with eGFR <50 mL/minute/1.73 m2, unless risk/benefit has been assessed. See "Dosage forms specific issues: Injection formulation." Evaluate renal function (particularly serum creatinine) at baseline and periodically during therapy. If increases occur, consider oral therapy. Monitor closely for breakthrough fungal infections in patients with severe renal impairment taking delayed-release tablets or oral suspension due to variability in posaconazole exposure.

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.

Dosage form specific issues:

• Benzyl alcohol and derivatives: Some dosage forms may contain sodium benzoate/benzoic acid; benzoic acid (benzoate) is a metabolite of benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension, and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol derivative with caution in neonates. See manufacturer’s labeling.

• Injection formulation: Do not give as an intravenous bolus injection. Avoid/limit use of IV formulation in patients with eGFR <50 mL/minute/1.73 m2; injection contains excipient cyclodextrin (sulfobutyl ether beta-cyclodextrin [SBECD]), which may accumulate; consider using oral posaconazole in these patients unless benefit of injection outweighs the risk. If injection is used in patients with eGFR <50 mL/minute, monitor serum creatinine closely; if increases occur, consider changing therapy to oral posaconazole.

• Oral formulations: The delayed-release tablet and oral suspension are not to be used interchangeably due to dosing differences for each formulation. Oral suspension contains glucose; patients with rare glucose-galactose malabsorption may require alternative agents.

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling.

Special populations:

• Obesity: Patients weighing >120 kg may have lower plasma drug exposure; monitor closely for breakthrough fungal infections.

• Patients taking posaconazole suspension who are unable to take or tolerate nutritional supplements or acidic carbonated beverages: Consider alternative antifungal therapy or closely monitor for breakthrough fungal infections in any patient unable to eat or tolerate an oral liquid nutritional supplement or acidic carbonated beverage (eg, ginger ale) and who does not have the option of taking the delayed-release tablet or injection.

Monitoring Parameters

Hepatic function (eg, AST/ALT, alkaline phosphatase and bilirubin) prior to initiation and during treatment; renal function, especially in patients on IV therapy if eGFR <50 mL/minute/1.73 m2; electrolyte disturbances (eg, calcium, magnesium, potassium); CBC; breakthrough fungal infections; adequate oral intake

Pregnancy Considerations

Adverse events have been observed 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 dyspepsia, constipation, lack of appetite, arthralgia, back pain, or insomnia. Have patient report immediately to prescriber signs of hypomagnesemia, signs of hypokalemia, signs of hypomagnesemia, hemoptysis, angina, tachycardia, significant dizziness, syncope, severe diarrhea, considerable nausea, dyspnea, excessive weight gain, edema of extremities, paresthesia, urinary retention, oliguria, chills, pharyngitis, significant headache, epistaxis, ecchymosis, vaginal hemorrhaging, severe asthenia, signs of liver impairment, or stomatitis (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 healthcare 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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