Posaconazole (Noxafil)
posaconazole
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Prophylaxis of invasive Aspergillus and Candida infections in severely immunocompromised patients (HSCT with GVHD, hematologic malignancies with prolonged neutropenia) | Adults and pediatrics ≥13 years (oral); ≥18 years (IV) | Prophylaxis | FDA Approved |
| Treatment of invasive aspergillosis | Adults and pediatrics ≥2 years (≥40 kg) for DR tablets; ≥18 years for IV | Monotherapy | FDA Approved |
| Oropharyngeal candidiasis (OPC) (oral suspension only) | Adults and pediatrics ≥13 years | Monotherapy | FDA Approved |
| Oropharyngeal candidiasis refractory to itraconazole and/or fluconazole (oral suspension only) | Adults and pediatrics ≥13 years | Salvage | FDA Approved |
Posaconazole is a second-generation triazole structurally related to itraconazole but with a broader antifungal spectrum. Its key clinical advantage over voriconazole is activity against Mucorales (agents of mucormycosis), making it a critical option when mucormycosis is in the differential diagnosis or as salvage therapy. Posaconazole is predominantly used for antifungal prophylaxis in high-risk immunocompromised patients, where it has demonstrated superiority over fluconazole in preventing invasive aspergillosis. Three formulations are available (delayed-release tablets, oral suspension, IV) that are NOT interchangeable due to different dosing and absorption profiles.
Salvage therapy for mucormycosis — when amphotericin B is intolerable or refractory. Evidence quality: Moderate
Salvage therapy for invasive aspergillosis — refractory to or intolerant of first-line agents (oral suspension formulation used in early salvage studies). Evidence quality: Moderate
Coccidioidomycosis — alternative for non-meningeal disease. Evidence quality: Low
Prophylaxis in solid organ transplant recipients — particularly lung transplant. Evidence quality: Moderate
Dosing
Adult Dosing by Clinical Scenario and Formulation
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Prophylaxis — IV formulation | 300 mg IV BID on Day 1 | 300 mg IV once daily | 300 mg/day | Infuse over ~90 minutes via central line (preferred) or peripheral line; use in-line filter Duration based on recovery from neutropenia or immunosuppression |
| Prophylaxis — delayed-release tablets | 300 mg (3 × 100 mg) BID on Day 1 | 300 mg once daily | 300 mg/day | Take with food; higher and more predictable exposure than oral suspension Preferred oral formulation for prophylaxis |
| Prophylaxis — oral suspension | 200 mg (5 mL) TID | 200 mg TID | 600 mg/day | Administer during or within 20 minutes of a full meal; if unable to eat, give with nutritional supplement or acidic carbonated beverage Formulations are NOT interchangeable |
| Invasive aspergillosis — treatment (IV or DR tablets) | 300 mg BID on Day 1 (IV or DR tablets) | 300 mg once daily | 300 mg/day | Duration based on clinical and mycological response; can switch IV to oral DR tablets when clinically appropriate |
| OPC — initial treatment (oral suspension only) | 100 mg (2.5 mL) BID on Day 1 | 100 mg once daily × 13 days | 200 mg/day (Day 1 only) | Total treatment: 14 days (1 day loading + 13 days maintenance); administer with full meal |
| Refractory OPC (oral suspension only) | 400 mg (10 mL) BID | 400 mg BID | 800 mg/day | Duration based on severity and clinical response; administer with full meal or nutritional supplement |
Posaconazole oral suspension, delayed-release tablets, and IV formulation use different dosing regimens and have different pharmacokinetic profiles. The DR tablets provide higher and more consistent drug exposure than the oral suspension, especially in patients who cannot eat or who are taking acid-suppressing medications. The oral suspension absorption is highly food-dependent and erratic in immunocompromised patients. When clinically feasible, DR tablets or IV are preferred over the oral suspension for prophylaxis to ensure adequate drug exposure.
TDM is recommended for posaconazole, particularly when using the oral suspension formulation. Target trough: ≥0.7 mcg/mL for prophylaxis (based on exposure-response analyses from the prophylaxis clinical trials). For treatment of invasive infections, higher troughs (≥1.0–1.25 mcg/mL) may be needed. An upper safety limit of 3.75 mcg/mL has been used as a benchmark during development of newer formulations. The DR tablet formulation produces more predictable levels, potentially reducing the need for routine TDM, though monitoring remains advisable in patients with severe GI disease, mucositis, or diarrhea that may impair absorption.
Pharmacology
Mechanism of Action
Posaconazole is a second-generation triazole antifungal that inhibits fungal lanosterol 14α-demethylase (CYP51), blocking ergosterol synthesis and disrupting fungal cell membrane integrity. Structurally related to itraconazole, posaconazole has broader antifungal coverage including activity against Aspergillus, Candida (including fluconazole-resistant species), Cryptococcus neoformans, dimorphic fungi, dermatophytes, and notably the Mucorales order (Rhizopus, Mucor, Lichtheimia), which distinguishes it from voriconazole. In vitro, posaconazole demonstrates fungicidal activity against Aspergillus species. Unlike many other azoles, posaconazole is not metabolized through CYP450 enzymes but is instead metabolized via phase 2 UDP-glucuronosyltransferase conjugation. However, posaconazole is a potent CYP3A4 inhibitor, creating a clinically important interaction profile despite its own non-CYP metabolism.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Oral suspension: highly variable, food-dependent (up to 4× increase with high-fat meal), saturable above 800 mg/day; DR tablets: higher and more consistent exposure, less food-dependent; Tmax 4–5 h (tablets), 5–8 h (suspension) | Oral suspension must be taken with a full meal; DR tablets preferred when predictable exposure is needed; DR tablets less affected by acid-suppressing medications or GI conditions |
| Distribution | Vd/F ~5–25 L/kg (apparent); protein binding >98% (albumin); extensive tissue distribution including lung, liver, kidney | Large Vd suggests wide tissue penetration; limited CSF data but clinical responses reported in CNS infections; highly protein-bound means free drug fraction is low |
| Metabolism | Primarily phase 2 via UGT1A4 (glucuronidation); NOT a CYP450 substrate; no significant oxidative metabolites; P-gp substrate; strong CYP3A4 inhibitor | CYP3A4 inducers (e.g., rifampin, phenytoin, efavirenz) can reduce posaconazole levels via P-gp/UGT induction despite non-CYP metabolism; posaconazole inhibits CYP3A4 causing major drug interactions |
| Elimination | t½ 25–35 h; feces 66% (parent compound); urine <1% unchanged; steady state ~7 days (DR tablets); not dialyzable | Long half-life supports once-daily maintenance dosing; primarily fecal elimination means renal impairment does not affect oral dosing; IV vehicle (SBECD) accumulates in renal impairment |
Side Effects
Adverse event data are derived from multiple clinical trial populations: 1844 patients receiving oral suspension (including 605 in prophylaxis trials), 230 patients receiving DR tablets in prophylaxis, and patients in the IV/DR tablet treatment trial. Incidence rates vary by formulation, indication, and underlying patient population.
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Diarrhea | Up to 42% (varies by study); >25% (DR tablets); 32% (IV phase) | Most common GI complaint; may impair oral suspension absorption, creating a vicious cycle of reduced drug levels; monitor for dehydration |
| Nausea | Up to 38%; >25% (DR tablets); 19% (IV phase) | Most common reason for discontinuation of DR tablets (2%); consider antiemetics if persistent |
| Pyrexia (fever) | >30% (oral susp prophylaxis); >25% (DR tablets); 21% (IV phase) | Distinguish from underlying infection or febrile neutropenia; common in this immunocompromised population |
| Vomiting | Up to 29% | May affect absorption of oral formulations; consider IV formulation if vomiting is persistent |
| Hypokalemia | 22% (IV phase); variable in oral studies | Correct potassium before and during therapy; important for QT prolongation risk reduction |
| Headache | Up to 28% (rOPC pool) | Generally manageable with simple analgesics |
| Rash | Up to 24% | More common in immunocompromised patients; monitor for progression |
| Abdominal pain | Up to 27% | Evaluate for underlying GI pathology in immunocompromised patients |
| LFT elevations | 24% (DR tablet study) | Generally mild and without clinical sequelae; not associated with higher plasma posaconazole concentrations |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Hepatotoxicity (cholestasis, hepatic failure, including fatal cases) | Rare; primarily at 800 mg/day oral suspension dose | Days to weeks | Monitor LFTs at baseline and during therapy; discontinue if clinical signs of liver disease develop; fatalities mainly in patients with serious underlying conditions |
| QT prolongation / Torsades de pointes | Rare; one clinical trial case with multiple contributing risk factors | Any time during therapy | Correct electrolytes (K+, Mg2+, Ca2+) before and during therapy; contraindicated with pimozide and quinidine; caution with other QT-prolonging agents |
| Pseudoaldosteronism | Rare (post-marketing) | Variable | Monitor blood pressure and potassium; manifests as hypertension, hypokalemia, low renin/aldosterone, elevated 11-deoxycortisol; consider discontinuation or aldosterone receptor antagonist |
| Hemolytic uremic syndrome / TTP | Very rare | Variable | Immediate hematology referral; discontinue posaconazole |
| Adrenal insufficiency | Rare | Weeks to months | Posaconazole inhibits corticosteroid metabolism via CYP3A4; monitor for fatigue, hypotension, electrolyte disturbances in patients on concurrent corticosteroids |
The high incidence rates for adverse events such as fever, diarrhea, and nausea reflect the severely immunocompromised patient population studied (post-HSCT, neutropenic, advanced HIV). Many of these events are related to underlying disease, concomitant chemotherapy, or GVHD rather than posaconazole itself. Rates were generally similar between posaconazole and comparator arms (fluconazole/itraconazole) in the prophylaxis trials, suggesting much of the reported toxicity is background noise in this population.
Drug Interactions
Posaconazole is a strong CYP3A4 inhibitor despite not being metabolized by CYP450 enzymes itself. It is metabolized via UGT and is a P-gp substrate. Drugs that induce UGT or P-gp (e.g., rifampin, phenytoin, efavirenz) can significantly reduce posaconazole levels. Conversely, posaconazole dramatically raises levels of CYP3A4 substrates.
Monitoring
- Posaconazole Trough LevelAt steady state (~7 days); repeat if clinical concern
RoutineTarget ≥0.7 mcg/mL for prophylaxis; ≥1.0–1.25 mcg/mL for treatment. Especially important with oral suspension (erratic absorption) and in patients with GI disease, diarrhea, or mucositis. DR tablets generally achieve adequate levels without routine TDM, but monitoring is still advisable in high-risk situations. - Hepatic Function (LFTs)Baseline; during therapy
RoutineLFT elevations observed in up to 24% of patients. Generally mild and reversible. Discontinue if clinical signs of liver disease develop. Serious hepatic reactions (including fatal) reported mainly at 800 mg/day oral suspension doses. - Electrolytes (K+, Mg2+, Ca2+)Baseline; during therapy
RoutineHypokalemia common (up to 22% in IV studies). Correct before and during therapy to reduce QT prolongation risk. Monitor for pseudoaldosteronism (hypokalemia + hypertension + low renin/aldosterone). - Renal FunctionBaseline; periodically during IV therapy
RoutineIV vehicle (SBECD) accumulates in moderate-severe renal impairment (eGFR <50). Monitor serum creatinine during IV administration; switch to oral when possible. Oral formulations do not require renal dose adjustment. - Blood PressurePeriodically
Trigger-basedPost-marketing reports of pseudoaldosteronism with new-onset or worsening hypertension. Investigate if hypertension and hypokalemia develop together. - Calcineurin Inhibitor LevelsFrequently during and after posaconazole therapy
RoutineTacrolimus and cyclosporine levels rise significantly with posaconazole; nephrotoxicity and leukoencephalopathy (including deaths) reported. Reduce calcineurin inhibitor dose at initiation and re-escalate when posaconazole is stopped.
Contraindications & Cautions
Absolute Contraindications
- Hypersensitivity to posaconazole or other azole antifungal agents
- Coadministration with sirolimus — ~9-fold increase in sirolimus levels
- Coadministration with CYP3A4 substrates that prolong QT — pimozide, quinidine
- Coadministration with ergot alkaloids (ergotamine, dihydroergotamine)
- Coadministration with venetoclax during dose initiation and ramp-up in CLL/SLL
- Hereditary fructose intolerance (HFI) — PowderMix formulation contains sorbitol
Relative Contraindications (Specialist Input Recommended)
- Pregnancy — animal data show skeletal malformations; use only if benefit outweighs risk
- Moderate-severe renal impairment with IV formulation — SBECD vehicle accumulates; use oral formulation when possible
Use with Caution
- Proarrhythmic conditions — electrolyte imbalances, concurrent QT-prolonging drugs, cardiomyopathy
- Hepatic impairment — no specific dose adjustment but monitor LFTs closely; limited data
- Concurrent calcineurin inhibitors — dose reduction and frequent level monitoring required (nephrotoxicity, leukoencephalopathy)
- GI conditions impairing absorption (oral suspension) — severe diarrhea, mucositis, GVHD of the gut; consider DR tablets or IV
- Concurrent CYP3A4 inducers — may reduce posaconazole to sub-therapeutic levels
Posaconazole significantly increases cyclosporine and tacrolimus concentrations, with cases of nephrotoxicity and leukoencephalopathy (including isolated deaths) reported. Reduce calcineurin inhibitor dose at initiation of posaconazole and monitor trough levels frequently. Posaconazole has been shown to prolong the QTc interval, and cases of Torsades de pointes have been reported. Correct potassium, magnesium, and calcium before starting therapy. Do not coadminister with CYP3A4 substrates known to prolong QT interval (pimozide, quinidine).
Patient Counselling
Purpose of Therapy
Posaconazole is an antifungal medication used to prevent or treat serious fungal infections. It is most commonly prescribed to prevent fungal infections in people whose immune systems are weakened by chemotherapy or bone marrow transplantation. Different forms of the medication (tablets, liquid, IV) work differently and cannot be switched without medical guidance.
How to Take
Delayed-release tablets should be taken with food for best absorption. Swallow tablets whole — do not crush, chew, or break them. The oral liquid suspension must be taken during or immediately after a full meal. If unable to eat, take it with a nutritional supplement drink. Shake the suspension well before each dose and use the provided dosing spoon. The different forms of posaconazole use different doses — never switch between them without your prescriber’s direction.
Sources
- Merck Sharp & Dohme. NOXAFIL (posaconazole) Prescribing Information (revised 2024). U.S. Food and Drug Administration. accessdata.fda.govComprehensive prescribing information covering all four formulations (injection, DR tablets, oral suspension, PowderMix), approved indications, dosing, adverse reactions from prophylaxis and treatment trials, and drug interactions.
- Merck Sharp & Dohme. NOXAFIL (posaconazole) Prescribing Information (2021 revision). accessdata.fda.govLabel revision adding treatment of invasive aspergillosis indication for IV and DR tablet formulations.
- Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med. 2007;356(4):348-359. doi:10.1056/NEJMoa061094Landmark RCT demonstrating posaconazole superiority over fluconazole/itraconazole for preventing IFIs and reducing all-cause mortality in neutropenic patients with AML/MDS.
- Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med. 2007;356(4):335-347. doi:10.1056/NEJMoa061098RCT showing posaconazole was non-inferior to fluconazole for overall IFI prophylaxis in GVHD patients and superior in preventing invasive aspergillosis.
- Patterson TF, Thompson GR 3rd, Denning DW, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the IDSA. Clin Infect Dis. 2016;63(4):e1-e60. doi:10.1093/cid/ciw326IDSA guideline recommending posaconazole for antifungal prophylaxis in high-risk patients and as salvage therapy for invasive aspergillosis.
- Maertens JA, Rahav G, Lee DG, et al. Posaconazole versus voriconazole for primary treatment of invasive aspergillosis: a phase 3, randomised, controlled, non-inferiority trial. Lancet. 2021;397(10273):499-509. doi:10.1016/S0140-6736(21)00219-1Phase 3 non-inferiority trial supporting the 2021 FDA approval of posaconazole IV/DR tablets for treatment of invasive aspergillosis.
- Schiller DS, Fung HB. Posaconazole: an extended-spectrum triazole antifungal agent. Clin Ther. 2007;29(9):1862-1886. doi:10.1016/j.clinthera.2007.09.015Comprehensive review of posaconazole pharmacology, spectrum of activity (including Mucorales), and clinical trial data supporting its use in prophylaxis and salvage therapy.
- Torres HA, Hachem RY, Chemaly RF, Kontoyiannis DP, Raad II. Posaconazole: a broad-spectrum triazole antifungal. Lancet Infect Dis. 2005;5(12):775-785. doi:10.1016/S1473-3099(05)70297-8Early review establishing the unique spectrum of posaconazole including anti-Mucorales activity and its differentiation from voriconazole.
- Andes D, Pascual A, Marchetti O. Antifungal therapeutic drug monitoring: established and emerging indications. Antimicrob Agents Chemother. 2009;53(1):24-34. doi:10.1128/AAC.00705-08Key TDM reference establishing the relationship between posaconazole trough concentrations and prophylactic efficacy, supporting the ≥0.7 mcg/mL target.
- Kraft WK, Chang PS, van Iersel ML,”; Waskin H, Krishna G, Kersemaekers WM. Posaconazole tablet pharmacokinetics: lack of effect of concomitant medications altering gastric pH and gastric motility in healthy subjects. Antimicrob Agents Chemother. 2014;58(7):4020-4025. doi:10.1128/AAC.02448-13Study demonstrating that DR tablet pharmacokinetics are not significantly affected by PPIs or metoclopramide, a key advantage over the oral suspension.
- Sansone-Parsons A, Krishna G, Simon J, et al. Effects of age, gender, and race/ethnicity on the pharmacokinetics of posaconazole in healthy volunteers. Antimicrob Agents Chemother. 2007;51(2):495-502. doi:10.1128/AAC.00472-06Population PK study confirming no significant effect of age, gender, or race on posaconazole pharmacokinetics, supporting the same dosing across demographics.
- Abulrob AN, Tayyem RF, Ghorab DS. Pharmacokinetic/pharmacodynamic profile of posaconazole. Clin Pharmacokinet. 2010;49(6):379-396. doi:10.2165/11319580-000000000-00000Comprehensive PK/PD review establishing key parameters: protein binding >98%, t½ 15–35 hours, Vd/F 5–25 L/kg, fecal elimination 66%, and the free-drug AUC/MIC as the primary PD predictor.
- Durani U, Tosh PK, Barreto JN, Estes LL, Jannetto PJ, Tande AJ. Retrospective comparison of posaconazole levels in patients taking the delayed-release tablet versus the oral suspension. Antimicrob Agents Chemother. 2015;59(8):4914-4918. doi:10.1128/AAC.00496-15Real-world study demonstrating significantly higher and more consistent posaconazole trough concentrations with DR tablets compared to oral suspension in immunocompromised patients.