CRESEMBA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for CRESEMBA (CRESEMBA).
Isavuconazole, the active moiety of CRESEMBA, inhibits fungal cytochrome P450-dependent 14-alpha-demethylase, thereby blocking the conversion of lanosterol to ergosterol, disrupting fungal cell membrane synthesis and function.
| Metabolism | Isavuconazole is metabolized primarily via UDP-glucuronidation (UGT) and to a minor extent by CYP3A4, CYP3A5, and CYP2C8. |
| Excretion | Fecal: ~76% (primarily as unchanged drug); Renal: <1% (unchanged); Biliary: Not a major route; Metabolism via CYP3A4 to inactive metabolites eliminated fecally. |
| Half-life | Terminal elimination half-life is approximately 24 hours (range 20-30 hours) after oral administration, supporting once-daily dosing; steady-state achieved by Day 4-5. |
| Protein binding | Isavuconazole is >99% bound to plasma proteins, predominantly albumin. |
| Volume of Distribution | Volume of distribution is approximately 450 L (or ~6.4 L/kg based on 70 kg), indicating extensive tissue penetration (e.g., lung, CNS). |
| Bioavailability | Oral bioavailability is 98% (high, allowing IV-to-oral switch without dose adjustment); food does not affect absorption. |
| Onset of Action | Oral: Time to peak plasma concentration ~4-5 hours; IV: End of infusion; Clinical effect onset varies by indication, typically within 24-48 hours for invasive aspergillosis. |
| Duration of Action | Duration of therapeutic effect is approximately 24 hours due to once-daily dosing; maintains trough concentrations above MIC for susceptible pathogens throughout dosing interval. |
200 mg intravenously every 8 hours for the first 48 hours (6 doses), then 200 mg intravenously once daily; or 200 mg orally three times daily for the first 48 hours (6 doses), then 200 mg orally once daily.
| Dosage form | CAPSULE |
| Renal impairment | For CrCl <30 mL/min: intravenous use is not recommended due to accumulation of the excipient SBECD; oral dosing does not require adjustment. |
| Liver impairment | Child-Pugh A or B: no adjustment necessary; Child-Pugh C: no data available, use with caution. |
| Pediatric use | Safety and efficacy not established in pediatric patients <18 years; no recommended dosing. |
| Geriatric use | No dose adjustment required based on age alone; monitor renal function as elderly patients may have decreased CrCl. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for CRESEMBA (CRESEMBA).
| Breastfeeding | No data on human milk; present in animal milk. M/P ratio not determined. Caution due to potential for infant exposure and adverse effects. |
| Teratogenic Risk | Pregnancy Category D. First trimester: In animals, skeletal and visceral anomalies. Second and third trimesters: Based on animal data, there is risk of fetal harm. Avoid use unless benefit outweighs risk. |
| Fetal Monitoring |
■ FDA Black Box Warning
No FDA black box warning.
| Serious Effects |
["Hypersensitivity to isavuconazole or any excipient","Concurrent use with strong CYP3A4/5 inducers (e.g., rifampin, carbamazepine, St. John's wort)","Concurrent use with high-dose ritonavir (>200 mg every 12 hours) or ketoconazole"]
| Precautions | ["Hepatic adverse reactions: elevations in liver enzymes, hepatitis, cholestasis, hepatic failure; monitor liver function tests.","Infusion-related reactions: hypotension, dyspnea, chills, headache; discontinue infusion if severe.","Hypersensitivity: serious cutaneous reactions including Stevens-Johnson syndrome.","Embryo-fetal toxicity: may cause fetal harm; advise females of reproductive potential of potential risk.","Drug-drug interactions: avoid coadministration with strong CYP3A4/5 inducers (e.g., rifampin, carbamazepine, St. John's wort) due to reduced isavuconazole exposure."] |
| Food/Dietary | Grapefruit and grapefruit juice should be avoided due to CYP3A4 inhibition. High-fat meals may decrease absorption, but consistent timing with or without food is acceptable. Avoid alcohol due to potential hepatotoxicity. |
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| Monitor liver function, renal function, electrolytes, and signs of pancreatitis. Fetal monitoring with ultrasound if used in pregnancy. |
| Fertility Effects | Animal studies show no impairment of fertility in males or females at clinically relevant doses. |
| Clinical Pearls | Monitor liver function tests closely; hepatotoxicity is a known adverse effect. Cresemba (isavuconazole) is a prodrug activated by esterases. It has a long half-life (~130 hours) allowing once-daily dosing after loading. It is a sensitive CYP3A4 substrate and a mild inhibitor; avoid coadministration with strong CYP3A4 inducers or inhibitors. Therapeutic drug monitoring is not routinely required. It has fewer drug interactions than voriconazole and does not cause QTc prolongation. Administration with food reduces absorption; take with or without food consistently. |
| Patient Advice | Take exactly as prescribed; do not skip doses or stop early. · Swallow capsules whole; do not crush or chew. · Take with or without food, but be consistent to maintain stable blood levels. · Avoid grapefruit and grapefruit juice during treatment. · Report any signs of liver problems (yellowing skin/eyes, dark urine, abdominal pain) immediately. · May cause nausea, vomiting, or diarrhea; inform your doctor if these become severe. · This medication can harm a fetus; use effective contraception during treatment and for 4 weeks after last dose. · Tell your doctor about all other medications, including over-the-counter and herbal products. · Do not drink alcohol while taking this medication. |