POSACONAZOLE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for POSACONAZOLE (POSACONAZOLE).
Posaconazole inhibits fungal CYP450-dependent 14α-demethylase, blocking ergosterol synthesis, disrupting fungal cell membrane integrity and function.
| Metabolism | Primarily hepatic via UDP-glucuronidation (UGT1A4); minor CYP450 involvement (CYP3A4); approximately 77% excreted unchanged in feces. |
| Excretion | Fecal (77% as unchanged drug) and renal (14% as glucuronide conjugates); <1% excreted unchanged in urine. |
| Half-life | Terminal elimination half-life: 35 hours (range 25–50 hours), allowing once-daily dosing after steady state; prolonged in hepatic impairment. |
| Protein binding | 98–99% bound to serum albumin. |
| Volume of Distribution | Vd: 177 L (2.5 L/kg), indicating extensive tissue distribution. |
| Bioavailability | Oral: 46% (delayed-release tablets) to <20% (suspension without high-fat meal); IV: 100%. |
| Onset of Action | Oral: 2–3 days to reach steady state; clinical effect may lag due to drug accumulation. |
| Duration of Action | 24 hours (once-daily dosing); continuous coverage after steady state. |
| Molecular Weight | 700.77 |
300 mg orally twice daily on day 1, then 300 mg once daily thereafter. Extended-release tablets: 300 mg orally twice daily on day 1, then 300 mg once daily. Intravenous: 300 mg IV twice daily on day 1, then 300 mg once daily.
| Dosage form | TABLET, DELAYED RELEASE |
| Renal impairment | No dose adjustment for mild to moderate renal impairment (CrCl ≥20 mL/min). For severe renal impairment (CrCl <20 mL/min), use with caution due to limited data; consider alternative therapy or monitor closely. |
| Liver impairment | Child-Pugh A and B: No dose adjustment required. Child-Pugh C: Limited data; use with caution and monitor for toxicity. |
| Pediatric use | For patients 2 years and older: For prophylaxis, 6 mg/kg/dose (max 300 mg) orally twice daily on day 1, then 6 mg/kg/dose (max 300 mg) once daily. For treatment of invasive aspergillosis, dosing per clinical guidelines. |
| Geriatric use | No specific dose adjustment required; select dose cautiously due to greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. |
| 1st trimester | Avoid unless essential. Teratogenic potential unknown; animal studies show fetal toxicity at high doses. |
| 2nd trimester | Use only if benefit outweighs risk. Limited human data; possible risk of skeletal anomalies. |
| 3rd trimester | Use cautiously. May cause prolonged QT interval in neonate if used near term. |
Clinical note
Comprehensive clinical and safety monograph for POSACONAZOLE (POSACONAZOLE).
| Placental transfer | Crosses placenta; human data show low cord blood concentrations (approximately 10-15% of maternal serum levels). |
| Breastfeeding | Excreted in human milk in small amounts. Monitor infant for jaundice, diarrhea, or rash. Weigh risk vs. benefit. |
| Lactation Rating |
■ FDA Black Box Warning
None.
| Serious Effects |
Hypersensitivity to posaconazole or other azolesCoadministration with CYP3A4 substrates that prolong QT interval (e.g., pimozide, quinidine)Coadministration with HMG-CoA reductase inhibitors that are metabolized by CYP3A4 (e.g., simvastatin, atorvastatin)
| Precautions | Hepatotoxicity: monitor liver function at baseline and during therapy, Electrolyte abnormalities: correct potassium, magnesium, and calcium before use, QT prolongation: avoid with other QT-prolonging drugs, monitor ECG if risk factors present, Drug-drug interactions: CYP3A4 substrate and inhibitor; avoid strong CYP3A4 inducers, Use in pregnancy only if benefit outweighs risk (limited data) |
| Food/Dietary | Take with high-fat meal or nutritional supplement; enhanced absorption with food. Avoid grapefruit and grapefruit juice. Do not take with antacids or acid-suppressing medications (PPIs, H2 blockers). |
Loading safety data…
| L3 (Moderately Safe) |
| Teratogenic Risk | FDA Pregnancy Category C. In animal studies, posaconazole caused skeletal malformations and embryotoxicity at doses below human exposure at therapeutic doses. Human data are limited; however, posaconazole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. First trimester: limited data, theoretical risk based on mechanism (CYP51 inhibition). Second and third trimesters: no specific human data; risk cannot be excluded. |
| Fetal Monitoring | Monitor maternal liver function tests (ALT, AST, bilirubin) at baseline and periodically due to risk of hepatotoxicity. Monitor serum posaconazole trough levels (target >0.7 µg/mL for prophylaxis, >1.0 µg/mL for treatment) to ensure therapeutic efficacy and avoid toxicity. For fetal monitoring, consider ultrasound for growth and anatomy if exposure occurs during first trimester. |
| Fertility Effects | Posaconazole has been shown to impair fertility in male rats at doses ≥1.25 times the human equivalent dose (based on AUC), with effects on sperm motility and morphology. In female rats, no significant fertility effects were observed at doses up to 3.5 times the human exposure. Human data on fertility are lacking; however, men should consider potential reversible effects on spermatogenesis. |
| Clinical Pearls | Must be taken with food or a nutritional supplement to enhance absorption; avoid with proton pump inhibitors. Monitor for QTc prolongation, especially with concurrent use of other QTc-prolonging agents. Check liver function tests weekly during first month of therapy. Therapeutic drug monitoring recommended for prophylaxis failure or suspected toxicity. Posaconazole is a strong inhibitor of CYP3A4; adjust doses of sensitive substrates like tacrolimus, sirolimus, and midazolam. |
| Patient Advice | Take each dose with a full meal or a nutritional supplement to ensure proper absorption. · Do not take with antacids or medications that reduce stomach acid (e.g., omeprazole). · Report any signs of liver problems: yellowing of skin or eyes, dark urine, or persistent nausea. · Contact your doctor immediately if you experience irregular heartbeat, fainting, or dizziness. · Avoid grapefruit and grapefruit juice while taking this medication. · Use effective contraception during treatment, as posaconazole can reduce hormonal contraceptive effectiveness. |