NOXAFIL
Clinical safety rating: caution
Comprehensive clinical and safety monograph for NOXAFIL (NOXAFIL).
Inhibits fungal cytochrome P450-dependent 14α-demethylase, blocking ergosterol synthesis and disrupting fungal cell membrane integrity.
| Metabolism | Primarily metabolized by UDP-glucuronidation (UGT1A4) and to a lesser extent via CYP3A4; substrate of P-glycoprotein. |
| Excretion | Primarily hepatic metabolism (glucuronidation) with extensive enterohepatic recirculation; renal excretion accounts for <1% as unchanged drug; approximately 71% of a radiolabeled dose is eliminated in feces (as parent drug and metabolites) and 13% in urine (as metabolites). |
| Half-life | Terminal elimination half-life is approximately 25-30 hours (range 20-66 hours) in healthy subjects; in patients with hepatic impairment or critical illness, half-life may be prolonged up to 40-50 hours; supports once-daily dosing in most patients. |
| Protein binding | Highly protein bound (>99%), primarily to albumin. |
| Volume of Distribution | Volume of distribution (Vd) is approximately 2.6 L/kg (range: 1.6-4.6 L/kg), indicating extensive tissue penetration; distributes widely into tissues including lungs, liver, and brain. |
| Bioavailability | Oral suspension: bioavailability is approximately 50% (range 35-70%) under fasted conditions; increased to 75-90% when administered with a high-fat meal; delayed-release tablet: absolute bioavailability is not determined but is approximately 54% relative to suspension; IV formulation: 100%. |
| Onset of Action | Oral suspension: time to steady-state is 6-7 days with twice-daily dosing; peak plasma concentrations achieved 3-5 hours after a single dose; clinical onset of antifungal effect is typically within 24-48 hours after achieving therapeutic levels. IV formulation: time to steady-state similar to oral. |
| Duration of Action | Effective therapeutic concentrations persist for 24 hours after a single dose; dosing interval is 12 hours for the oral suspension (loading dose) followed by 24 hours for maintenance; IV and tablet formulations are dosed once daily. |
Posaconazole oral suspension: 200 mg (5 mL) three times daily with food. Oral delayed-release tablets: 300 mg twice daily on day 1, then 300 mg once daily thereafter with food. IV: 300 mg twice daily on day 1, then 300 mg once daily.
| Dosage form | SUSPENSION |
| Renal impairment | No dose adjustment for mild to moderate renal impairment. Severe renal impairment (CrCl <20 mL/min): Use with caution; consider alternative therapy if possible due to potential accumulation of the vehicle (sulfobutylether β-cyclodextrin) in IV formulation. |
| Liver impairment | Mild to moderate hepatic impairment (Child-Pugh A or B): No dose adjustment. Severe hepatic impairment (Child-Pugh C): Use with caution; limited data, consider monitoring posaconazole levels. |
| Pediatric use | For prophylaxis of invasive fungal infections: Oral suspension: 200 mg (5 mL) three times daily for patients aged ≥13 years and weighing ≥34 kg. For those weighing <34 kg, 4.5 mg/kg/dose three times daily (max 300 mg/day). Tablets and IV: Safety and efficacy not established in patients <18 years. |
| Geriatric use | No specific dose adjustment recommended. Monitor renal function and consider potential for increased exposure due to age-related decline in renal function. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for NOXAFIL (NOXAFIL).
| Breastfeeding | It is unknown whether posaconazole is excreted in human breast milk. No M/P ratio data are available. Due to potential for serious adverse reactions in nursing infants, breastfeeding is not recommended during treatment and for at least 24 hours after the last dose. |
| Teratogenic Risk | Posaconazole (NOXAFIL) is classified as pregnancy category D. Animal studies have shown embryotoxicity and teratogenicity at doses lower than human therapeutic exposures. In the first trimester, there is a potential risk of skeletal and cardiac malformations. During the second and third trimesters, exposure may be associated with fetal growth restriction and increased risk of spontaneous abortion. Use only if potential benefit outweighs risk. |
■ FDA Black Box Warning
Do not use in patients with moderate or severe hepatic impairment (Child-Pugh class B or C) unless the benefit outweighs the risk.
| Serious Effects |
Hypersensitivity to posaconazole or excipients; concomitant use with CYP3A4 substrates that prolong QT interval (e.g., pimozide, quinidine); severe hepatic impairment.
| Precautions | Hepatotoxicity (elevated liver enzymes, hepatitis, cholestasis); QT prolongation; drug interactions with CYP3A4 substrates; increased risk of visual disturbances; renal impairment; electrolyte disturbances; hemolysis. |
Loading safety data…
| Fetal Monitoring | Monitor liver function tests (AST, ALT, bilirubin) and renal function periodically. Assess ECG for QTc prolongation, especially in patients with electrolyte abnormalities or concomitant QTc-prolonging drugs. Monitor trough serum posaconazole concentrations to ensure therapeutic levels, as pregnancy may alter pharmacokinetics. Perform serial fetal ultrasound to assess growth and anatomy. |
| Fertility Effects | In animal studies, posaconazole reduced fertility indices and increased pre-implantation loss. The clinical significance in humans is unknown. Women of childbearing potential should use effective contraception during treatment and for 4 weeks after discontinuation. |