SPORANOX
Clinical safety rating: caution
Comprehensive clinical and safety monograph for SPORANOX (SPORANOX).
Inhibits fungal cytochrome P450 (CYP450)-dependent lanosterol 14α-demethylase, blocking ergosterol synthesis and disrupting fungal cell membrane integrity.
| Metabolism | Primarily metabolized by hepatic CYP3A4 enzyme; metabolites include hydroxy-itraconazole. It is an inhibitor of CYP3A4. |
| Excretion | Itraconazole is extensively metabolized in the liver via CYP3A4 to active metabolites, including hydroxyitraconazole. The parent drug and metabolites are primarily excreted in feces (approximately 54%) and urine (approximately 35%), with less than 1% of the dose excreted unchanged in urine. |
| Half-life | The terminal elimination half-life of itraconazole ranges from 21 to 35 hours for single doses, increasing to approximately 34 to 42 hours at steady state. The half-life of the active metabolite, hydroxyitraconazole, is similar. This long half-life allows for once-daily or twice-daily dosing in most indications. |
| Protein binding | Itraconazole is highly protein-bound (99.8%), primarily to albumin. This high binding restricts distribution into tissues but contributes to its long half-life and extensive tissue penetration. |
| Volume of Distribution | The apparent volume of distribution (Vd/F) for itraconazole is large, approximately 10.7 L/kg, indicating extensive tissue distribution and high lipophilicity. This results in tissue concentrations several times higher than plasma concentrations, particularly in skin, nails, lungs, and adipose tissue. |
| Bioavailability | Oral bioavailability of itraconazole capsules is approximately 55% under fed conditions (especially with a full meal) but is variable (30-70%) and decreases significantly when taken on an empty stomach. The oral solution has higher and more consistent bioavailability (approximately 60-80%) and is better absorbed in the fasted state. Absorption is pH-dependent; therefore, concomitant use of acid-reducing agents reduces absorption. |
| Onset of Action | Oral: Time to peak plasma concentration (Tmax) is 2 to 5 hours. Clinical effect, such as antifungal activity, begins within 24 to 48 hours after the first dose, but therapeutic response may take several days to weeks depending on the infection site and severity. Intravenous: Not available in all formulations; onset is more rapid with IV administration. |
| Duration of Action | The duration of therapeutic effect is prolonged due to the long half-life and high tissue penetration. After discontinuation, therapeutic concentrations persist in tissues (e.g., skin, nails) for weeks to months, supporting pulse dosing regimens for onychomycosis. Clinical duration varies by indication: for dermatophytosis, treatment duration is typically 1 to 4 weeks; for systemic mycoses, months may be required. |
| Action Class | Fungal ergosterol synthesis inhibitor |
| Brand Substitutes | Itralase 100 Capsule, Canditral 100 Capsule, Syntran Capsule, Itrafree 100mg Capsule, Itromed 100 Capsule, Iycotizol Capsule |
200 mg orally twice daily for 3-7 days; for onychomycosis: 200 mg orally once daily for 12 weeks.
| Dosage form | SOLUTION |
| Renal impairment | No adjustment needed for GFR 15-50 mL/min; avoid use in GFR <15 mL/min. |
| Liver impairment | Child-Pugh A: 100 mg orally once daily; Child-Pugh B or C: avoid use. |
| Pediatric use | 5 mg/kg/day orally in two divided doses for systemic fungal infections; max 400 mg/day. |
| Geriatric use | Start at 100 mg orally once daily; increase cautiously based on response and tolerability. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for SPORANOX (SPORANOX).
| Breastfeeding | Itraconazole is excreted into human breast milk with an M/P ratio of approximately 3.5. Due to potential for adverse effects (e.g., hepatic toxicity) in nursing infants, breastfeeding is not recommended during treatment and for 7 days after last dose. |
| Teratogenic Risk | Pregnancy Category C. First trimester: Increased risk of major congenital malformations (e.g., skeletal, cardiac, CNS) based on animal studies; limited human data. Second/third trimester: Potential fetal toxicity (e.g., low birth weight, prematurity) observed in animal studies; use only if benefit outweighs risk. |
■ FDA Black Box Warning
Congestive heart failure (CHF): SPORANOX may cause or exacerbate CHF. Do not use for treatment of onychomycosis in patients with evidence of ventricular dysfunction (e.g., CHF history). Discontinue if signs/symptoms of CHF occur.
| Serious Effects |
Hypersensitivity to itraconazole or excipients. Treatment of onychomycosis in patients with CHF or ventricular dysfunction. Concurrent use with CYP3A4 substrates that prolong QT interval (e.g., quinidine, dofetilide, pimozide, methadone), HMG-CoA reductase inhibitors metabolized by CYP3A4 (e.g., simvastatin, lovastatin), triazolam, midazolam oral, ergot alkaloids, and certain other drugs (e.g., nisoldipine, eplerenone, colchicine in renal/hepatic impairment).
| Precautions | Hepatotoxicity (rare but severe, including liver failure). Negative inotropic effects leading to CHF. Hearing loss (reversible). Hypokalemia, edema, and pulmonary edema. Prolonged QT interval and arrhythmias. |
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| Fetal Monitoring | Monitor liver function tests (LFTs) monthly during treatment. Assess renal function, electrolytes, and CBC periodically. In pregnancy, consider ultrasound for fetal growth and anatomy if high-dose or prolonged therapy. |
| Fertility Effects | Animal studies show no significant impairment of fertility at therapeutic doses. In humans, no well-controlled studies; however, itraconazole may cause transient decreases in testosterone levels, potentially affecting spermatogenesis; clinical relevance unclear. |