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. |
| Molecular Weight | 448.94 |
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 | TOLSURA (tolvaptan) is contraindicated in pregnancy; based on animal data, can cause fetal harm. Avoid use during first trimester; consider alternative therapies. |
| 2nd trimester | Contraindicated in pregnancy; potential for teratogenicity and fetal renal effects. Not recommended during second trimester. |
| 3rd trimester | Contraindicated in pregnancy; risks include oligohydramnios and renal dysfunction. Avoid during third trimester. |
Clinical note
Comprehensive clinical and safety monograph for TOLSURA (TOLSURA).
| Placental transfer | Tolvaptan crosses the placenta in animal studies; human data are absent, but due to molecular weight (448.94 Da) and lipophilicity, placental transfer is expected. |
| Breastfeeding | It is unknown if tolvaptan is excreted in human milk. Due to potential serious adverse reactions in nursing infants, breastfeeding is not recommended while on TOLSURA. Consider the importance of the drug to the mother and discontinue breastfeeding or discontinue the drug. |
■ 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 tolvaptan or any componentAnuriaHypernatremiaInability to sense or respond to thirstHypovolemiaConcomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole)
| 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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| Lactation Rating | L5 |
| 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. |
| 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. |
| Food/Dietary | High-fat meals delay absorption and reduce peak concentration; avoid taking with or shortly after a high-fat meal. Grapefruit juice may increase suvorexant levels (by CYP3A4 inhibition); avoid concurrent use. Alcohol increases risk of central nervous system depression and should be avoided. |
| Clinical Pearls | TOLSURA (suvorexant) is a dual orexin receptor antagonist (DORA) for insomnia. Onset within 30 minutes; avoid high-fat meals which delay absorption. Use lowest effective dose (10-15 mg) to minimize next-day somnolence. Contraindicated in narcolepsy. Can cause complex sleep behaviors. Not recommended in patients with severe hepatic impairment. |
| Patient Advice | Take only when you have at least 7 hours to dedicate to sleep. · Do not take with or immediately after a high-fat meal as it reduces absorption. · Avoid alcohol and other central nervous system depressants while taking this medication. · You may experience next-day drowsiness; do not drive or operate machinery until you know how the drug affects you. · Report any unusual sleep behaviors such as sleepwalking or driving while not fully awake. |