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. |
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 | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for POSACONAZOLE (POSACONAZOLE).
| Breastfeeding | Posaconazole is excreted in human milk at low levels; the milk-to-plasma (M/P) ratio is not specifically reported. The relative infant dose is estimated to be <10% of maternal weight-adjusted dose based on limited data. Caution is advised; consider risk versus benefit, especially in premature or low-birth-weight infants. |
| 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. |
■ FDA Black Box Warning
None.
| Serious Effects |
["Hypersensitivity to posaconazole or any excipients","Concomitant use with ergot alkaloids","Concomitant use with sirolimus (increased sirolimus levels)","Coadministration with CYP3A4 substrates (e.g., pimozide, quinidine, lovastatin, simvastatin, atorvastatin) that have narrow therapeutic window"]
| 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)"] |
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| 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. |