TOLSURA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TOLSURA (TOLSURA).
TOLSURA (itraconazole) is a triazole antifungal agent that inhibits fungal cytochrome P450-dependent 14α-demethylase, thereby blocking the conversion of lanosterol to ergosterol, a key component of the fungal cell membrane. This disruption increases membrane permeability and inhibits fungal growth.
| Metabolism | Primarily metabolized by the liver via cytochrome P450 3A4 (CYP3A4) isoenzyme. Itraconazole is a strong inhibitor of CYP3A4 and also inhibits P-glycoprotein. The major metabolites are hydroxy-itraconazole, which has activity comparable to itraconazole, and others. |
| Excretion | Renal: 40% as unchanged drug; biliary/fecal: 51% (metabolites); total clearance: 99 mL/min. |
| Half-life | Terminal half-life: 29 hours (range 22-38 h). Supports once-daily dosing after initial loading. |
| Protein binding | 97% bound, primarily to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | 7.6 L/kg, indicating extensive tissue distribution. |
| Bioavailability | Oral: 55% (fasting); 70% with high-fat meal (1000 kcal, 50% fat). IV: 100%. |
| Onset of Action | Oral: 1-2 days for detectable levels; 4-7 days for steady-state clinical effect. |
| Duration of Action | 24 hours due to once-daily dosing; steady-state achieved in 4-7 days. |
TOLSURA (itraconazole) is administered orally as a 65 mg capsule. The standard adult dose is 130 mg (2 capsules) taken orally once daily with a full meal for the treatment of onychomycosis. Total duration is 1 week for toenail or fingernail infections.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment is required for mild to moderate renal impairment (CrCl >30 mL/min). For severe renal impairment (CrCl <30 mL/min), itraconazole is not recommended as the capsule formulation may result in reduced absorption and unpredictable pharmacokinetics. |
| Liver impairment | Itraconazole is contraindicated in patients with Child-Pugh Class C (severe) hepatic impairment. For Child-Pugh Class A or B, caution is advised; dose reduction should be considered based on liver function monitoring, though no specific dose guidelines are established. Itraconazole should be used only if the benefit outweighs the risk. |
| Pediatric use | Safety and efficacy in pediatric patients have not been established; no approved dosing guidelines exist for TOLSURA in children. |
| Geriatric use | No specific dose adjustment is recommended for elderly patients, but caution is advised due to age-related decline in hepatic, renal, or cardiac function. Itraconazole exposure may be increased; clinical monitoring for adverse effects is recommended. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for TOLSURA (TOLSURA).
| Breastfeeding | Itraconazole is excreted into human breast milk. The milk-to-plasma ratio (M/P) is approximately 0.1-0.3. Limited data indicate that the estimated infant dose is less than 1% of the maternal weight-adjusted dose. However, due to the potential for adverse effects in the nursing infant (e.g., hepatotoxicity, adrenal suppression), caution is advised. Consider temporary discontinuation of breastfeeding during therapy or use alternative antifungal therapy. |
| Teratogenic Risk | Pregnancy Category C. In animal studies, itraconazole (active ingredient of TOLSURA) caused dose-related maternal toxicity, embryotoxicity, and teratogenicity (major skeletal defects, encephaloceles, and macroglossia) at high doses. In humans, first-trimester exposure data are limited but suggest an increased risk of spontaneous abortion and major congenital malformations, including cardiovascular and musculoskeletal defects. Second and third trimester risks are less defined; however, itraconazole should be avoided during pregnancy unless potential benefit outweighs risk. |
■ FDA Black Box Warning
TOLSURA is contraindicated in patients with ventricular dysfunction, such as congestive heart failure (CHF) or a history of CHF, unless the benefit clearly outweighs the risk. It may cause or exacerbate CHF and should not be used in patients with evidence of ventricular dysfunction, unless necessary for life-threatening infections.
| Serious Effects |
["Hypersensitivity to itraconazole or any excipient","Congestive heart failure or history of CHF, including ventricular dysfunction","Coadministration with drugs metabolized by CYP3A4 that prolong QT interval or cause serious cardiac events (e.g., methadone, disopyramide, dofetilide, quinidine, isradipine, nisoldipine, pimozide, sertindole, telithromycin, ergot alkaloids, oral midazolam, triazolam, lovastatin, simvastatin, eplerenone, irinotecan, lurasidone, naloxegol, ranolazine, and others)","Coadministration with colchicine, fesoterodine, solifenacin, or ticagrelor in patients with renal or hepatic impairment"]
| Precautions | ["Congestive heart failure: Negative inotropic effects; avoid in patients with ventricular dysfunction unless benefit outweighs risk.","Hepatotoxicity: Cases of liver injury including fatal hepatic failure; monitor liver function tests.","Cardiac arrhythmias: QT prolongation and ventricular arrhythmias, especially when coadministered with other QT-prolonging drugs.","Neuropathy: Cases of peripheral neuropathy; discontinue if neurological symptoms develop.","Hypersensitivity: Anaphylaxis, Stevens-Johnson syndrome; discontinue if severe reactions occur.","Drug interactions: Strong CYP3A4 inhibitor; contraindicated with drugs metabolized by CYP3A4 that can cause QT prolongation or serious events (e.g., methadone, disopyramide, certain statins, midazolam, pimozide, etc.).","Hearing loss: Transient or permanent hearing loss reported.","Pregnancy: Avoid use during pregnancy unless benefit outweighs risk; embryotoxic and teratogenic in animal studies."] |
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| Fetal Monitoring | Monitor liver function tests (ALT, AST, bilirubin) and electrolytes (especially potassium, magnesium) periodically. Assess cardiac function (ECG) for QT prolongation, particularly in patients with pre-existing cardiac conditions or concurrent use of QTc-prolonging drugs. Monitor for signs of hepatotoxicity (jaundice, fatigue, right upper quadrant pain). In pregnancy, consider fetal ultrasound to assess for anomalies if exposure occurred during first trimester. |
| Fertility Effects | Itraconazole has been reported to cause alterations in spermatogenesis and reduced fertility in animal studies at high doses. In humans, reversible impairment of spermatogenesis (oligospermia, decreased sperm motility) has been observed with prolonged high-dose therapy. Effects on female fertility are not well documented, but itraconazole may inhibit ovarian steroidogenesis based on in vitro studies. Advise patients of potential reversible effects on fertility. |