DAURISMO
Clinical safety rating: caution
Comprehensive clinical and safety monograph for DAURISMO (DAURISMO).
Hedgehog pathway inhibitor; binds to and inhibits Smoothened (SMO), a transmembrane protein involved in Hedgehog signal transduction.
| Metabolism | Primarily metabolized by CYP3A4; also a substrate of P-glycoprotein (P-gp). |
| Excretion | Fecal (approximately 86% of total radioactivity) and renal (approximately 4% of total radioactivity). Unchanged drug accounts for about 68% of the administered dose in feces and <1% in urine. |
| Half-life | Terminal elimination half-life is approximately 230 hours (range 157-310 hours) in healthy subjects; the long half-life supports once-weekly dosing. |
| Protein binding | Approximately 99.9% bound, primarily to serum albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Apparent volume of distribution (Vd/F) is approximately 76 L (range 46-106 L) in patients; extensive tissue distribution consistent with lipophilic character. |
| Bioavailability | Absolute oral bioavailability is not determined; based on mass balance, oral absorption is complete with a high fraction absorbed (>90% of dose). |
| Onset of Action | Oral administration: symptomatic improvement in hemolysis (e.g., hemoglobin increase) observed as early as 2-4 weeks; peak effect on hemolysis occurs around 12 weeks. |
| Duration of Action | Sustained reduction in hemolysis and transfusion independence with continued weekly dosing; due to long half-life, pharmacodynamic effects persist for several weeks after discontinuation. |
100 mg orally once daily with or without food.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment recommended for mild to moderate renal impairment (eGFR >=30 mL/min). For severe renal impairment (eGFR <30 mL/min) or end-stage renal disease, reduce dose to 50 mg orally once daily. |
| Liver impairment | No dose adjustment recommended for mild hepatic impairment (Child-Pugh A). For moderate (Child-Pugh B) or severe (Child-Pugh C) hepatic impairment, reduce dose to 50 mg orally once daily. |
| Pediatric use | Safety and efficacy in pediatric patients have not been established. |
| Geriatric use | No specific dose adjustment recommended for elderly patients; however, monitor for increased risk of adverse effects due to age-related renal and hepatic decline. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for DAURISMO (DAURISMO).
| Breastfeeding | No data on presence in human milk, effects on breastfed infant, or milk production. Because of potential for serious adverse reactions (e.g., developmental toxicity), breastfeeding is not recommended during treatment and for at least 30 days after the last dose. |
| Teratogenic Risk | Pregnancy Category X. Based on its mechanism of action (Hedgehog pathway inhibitor), there is high risk of embryotoxicity and teratogenicity. Animal studies show fetal malformations and fetal death. Use is contraindicated in pregnant women. Effective contraception must be used during treatment and for at least 30 days after the last dose. |
■ FDA Black Box Warning
None.
| Serious Effects |
["None"]
| Precautions | ["Embryo-fetal toxicity: Can cause fetal harm; advise females of reproductive potential of the risk to a fetus and to use effective contraception.","QT prolongation: Can prolong QT interval; monitor electrocardiograms and electrolytes.","Severe infections: Increased risk of infections, including fatal infections.","Hemorrhage: Fatal and serious hemorrhagic events reported.","Hepatotoxicity: Can cause hepatic transaminase elevations; monitor liver function."] |
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| Fetal Monitoring | Pregnancy testing should be performed prior to initiation of therapy. Women of reproductive potential must use highly effective contraception during treatment and for 30 days after the last dose. If pregnancy occurs, report to manufacturer and consider fetal monitoring via ultrasound. |
| Fertility Effects | Animal studies indicate potential impairment of male and female fertility. No human data. Male patients with female partners of reproductive potential should use effective contraception during treatment and for 30 days after the last dose. |