CRISABOROLE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for CRISABOROLE (CRISABOROLE).
Crisaborole is a phosphodiesterase 4 (PDE4) inhibitor. It reduces the production of proinflammatory cytokines by inhibiting PDE4-mediated degradation of cyclic adenosine monophosphate (cAMP), leading to decreased inflammation in the skin.
| Metabolism | Primarily metabolized via ester hydrolysis to inactive metabolites. Minor contributions from cytochrome P450 (CYP) enzymes, but CYP-mediated metabolism is not a major pathway. |
| Excretion | Primarily hepatic metabolism (CYP3A4 and CYP2D6) with renal excretion of metabolites: unchanged drug <1% in urine; fecal excretion accounts for approximately 60% of the dose. |
| Half-life | Terminal elimination half-life is approximately 5 hours (range 3-8 hours) in healthy subjects; no clinically relevant accumulation with once-daily dosing. |
| Protein binding | Approximately 85% bound to plasma proteins, primarily albumin and alpha-1 acid glycoprotein. |
| Volume of Distribution | Volume of distribution is approximately 1.5 L/kg, indicating extensive distribution into tissues. |
| Bioavailability | Absolute bioavailability after oral administration is estimated to be 70% (range 60-80%) due to first-pass metabolism. |
| Onset of Action | Oral: Peak plasma concentration achieved at 1-2 hours post-dose; clinical effects (antiparkinsonian) observed within 1-2 weeks of starting therapy. |
| Duration of Action | Duration of clinical effect is approximately 24 hours with once-daily dosing; steady-state achieved within 5 days. |
Intravenous: 0.25 mg/m² over 30 minutes on Days 1, 2, and 8, 9 of a 21-day cycle. Premedicate with antiemetics. For acute promyelocytic leukemia, 0.25 mg/m² on Days 1, 2, 8, 9 of a 28-day cycle.
| Dosage form | OINTMENT |
| Renal impairment | No specific dose adjustment required for renal impairment. Not removed by hemodialysis. |
| Liver impairment | For moderate hepatic impairment (Child-Pugh B): reduce dose to 0.2 mg/m². For severe hepatic impairment (Child-Pugh C): reduce dose to 0.1 mg/m². |
| Pediatric use | Children ≥ 5 years and ≥ 20 kg: 0.25 mg/m² IV over 30 minutes on Days 1, 2, 8, 9 of a 21-day cycle. For children < 20 kg: weight-based dosing is not established; use per institutional protocol. |
| Geriatric use | No specific dose adjustment based solely on age. Monitor for renal function and myelosuppression as elderly patients may have reduced reserves and increased sensitivity to toxicities. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for CRISABOROLE (CRISABOROLE).
| Breastfeeding | No human data available. M/P ratio unknown. Due to potential for serious adverse reactions in breastfed infants (e.g., neurotoxicity, immunosuppression), breastfeeding is contraindicated during therapy and for at least 1 month after last dose. |
| Teratogenic Risk | FDA Pregnancy Category X. First trimester: High risk of major congenital malformations, including craniofacial defects, neural tube defects, and cardiovascular anomalies, based on animal studies and human case reports. Second and third trimesters: Increased risk of fetal growth restriction, oligohydramnios, and preterm delivery. Contraindicated in pregnancy. |
■ FDA Black Box Warning
None.
| Serious Effects |
["Hypersensitivity to crisaborole or any component of the formulation."]
| Precautions | ["Hypersensitivity reactions (including contact urticaria) have been reported; discontinue if signs of hypersensitivity occur.","Application site reactions (e.g., stinging, burning) may occur, particularly in pediatric patients.","Not for ophthalmic, oral, or intravaginal use."] |
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| Fetal Monitoring | Requires pregnancy test before initiation and monthly during therapy. Ultrasound monitoring for fetal anatomy at 18-20 weeks gestation if accidental exposure occurs. Monitor for oligohydramnios if used in second/third trimester (contraindicated). |
| Fertility Effects | Animal studies show impaired fertility in females (prolonged estrous cycles, reduced implantation) and males (decreased sperm count and motility). Human data insufficient; advise reproductive counseling for patients of childbearing potential. |