RYDAPT
Clinical safety rating: caution
Comprehensive clinical and safety monograph for RYDAPT (RYDAPT).
Midostaurin is a multi-targeted tyrosine kinase inhibitor that inhibits FLT3 (FMS-like tyrosine kinase 3) and additionally targets KIT, PDGFR, and other kinases involved in cell proliferation and survival.
| Metabolism | Primarily metabolized by CYP3A4. Active metabolites include CGP52421 and CGP62221. |
| Excretion | Primarily hepatobiliary elimination: ~78% of dose recovered in feces (largely as unchanged drug and metabolites), and ~14% in urine (mostly metabolites). |
| Half-life | Terminal elimination half-life approximately 19 hours (range 12–31 hours) at steady state, supporting twice-daily dosing. |
| Protein binding | Approximately 93% bound to plasma proteins, primarily albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Volume of distribution is approximately 800 L (based on population PK, ~10.7 L/kg for a 75 kg individual), indicating extensive tissue distribution. |
| Bioavailability | Oral bioavailability is approximately 15–25% due to first-pass metabolism; absorption is enhanced with a high-fat meal. |
| Onset of Action | Oral: clinical response observed within 2–4 weeks of continuous dosing; maximal cytoreduction may require 2–3 months. |
| Duration of Action | Dosing interval is 12 hours; sustained exposure over 24 hours with regular twice-daily administration. Continuous treatment is required to maintain response. |
400 mg orally twice daily with food.
| Dosage form | CAPSULE |
| Renal impairment | No dose adjustment required for GFR ≥30 mL/min; not recommended in GFR <30 mL/min or ESRD. |
| Liver impairment | Child-Pugh A: no adjustment; Child-Pugh B: reduce to 200 mg twice daily; Child-Pugh C: not recommended. |
| Pediatric use | Not approved in pediatric patients; safety and efficacy not established. |
| Geriatric use | No specific geriatric dose adjustment; monitor for adverse effects due to age-related decline. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for RYDAPT (RYDAPT).
| Breastfeeding | No human data available; midostaurin and its metabolites are likely excreted in human milk due to low molecular weight and lipophilicity. M/P ratio unknown. Because of potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment and for at least 4 months after last dose. |
| Teratogenic Risk | Based on mechanism of action (inhibition of FLT3, KIT, and PDGFR) and animal studies, midostaurin is embryotoxic and teratogenic. In pregnant rats, doses below the clinical exposure caused increased post-implantation loss, reduced fetal body weight, and malformations including skeletal and visceral anomalies. Use is contraindicated in pregnancy unless no safer alternative; effective contraception required in women of reproductive potential during treatment and for at least 4 months after last dose. |
■ FDA Black Box Warning
None.
| Serious Effects |
None.
| Precautions | ["Pulmonary toxicity (interstitial lung disease, pneumonitis)","Embryo-fetal toxicity (can cause fetal harm)","Hepatotoxicity (elevated liver enzymes)","QT interval prolongation (monitor electrolytes and ECG)"] |
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| Fetal Monitoring | Pregnancy test prior to initiation in women of reproductive potential. Monitor for myelosuppression (CBC with differential weekly for first month, then monthly), hepatotoxicity (LFTs at baseline and monthly), and pancreatitis (amylase/lipase at baseline and monthly). Fetal ultrasound if inadvertently exposed during pregnancy. |
| Fertility Effects | In animal studies, midostaurin caused disruption of estrous cycles and reduced fertility in female rats at exposures similar to clinical levels; no data on male fertility. Human data are lacking; may impair female fertility based on mechanism. |