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. |
| Molecular Weight | 558.65 |
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 | Avoid; midkine inhibitor with potential for embryotoxicity; animal studies show teratogenicity. |
| 2nd trimester | Avoid; may cause fetal harm; limited human data. |
| 3rd trimester | Avoid; risk of fetal toxicity outweighs benefit. |
Clinical note
Comprehensive clinical and safety monograph for RYDAPT (RYDAPT).
| Placental transfer | Crosses placenta in animal models; likely crosses human placenta given molecular weight and lipophilicity. |
| Breastfeeding | Not recommended; due to potential for serious adverse reactions in nursing infants, advise women not to breastfeed during treatment and for at least 1 week after last dose. |
| Lactation Rating |
■ FDA Black Box Warning
None.
| Serious Effects |
Hypersensitivity to midostaurin or any excipients
| 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) |
| Food/Dietary | Take with food to reduce nausea. Avoid grapefruit and grapefruit juice (strong CYP3A4 inhibitors) due to risk of increased midostaurin exposure. Avoid St. John's wort (strong CYP3A4 inducer) as it may reduce efficacy. |
| Clinical Pearls |
Loading safety data…
| L5 |
| 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. |
| 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. |
| RYDAPT (midostaurin) is an oral FLT3 and multi-kinase inhibitor. It is used in combination with standard cytarabine and daunorubicin induction and consolidation therapy for newly diagnosed FLT3-mutated AML, and as monotherapy for aggressive systemic mastocytosis (ASM), SM-AHN, or mast cell leukemia. Monitor for QTc prolongation; obtain ECG prior to initiation and periodically. Assess ejection fraction before treatment due to risk of left ventricular dysfunction. Midostaurin is a moderate CYP3A4 inhibitor; caution with sensitive CYP3A4 substrates. Avoid concomitant use with strong CYP3A4 inducers (e.g., rifampin) as they may reduce midostaurin efficacy. Pre-medicate with antiemetics to reduce nausea/vomiting. |
| Patient Advice | Take RYDAPT exactly as prescribed, usually twice daily with food to reduce nausea. · Do not crush or open capsules; swallow whole. · If you vomit after taking a dose, do not take an extra dose; wait until the next scheduled dose. · You may experience serious side effects including lung inflammation (cough, fever, trouble breathing), heart problems (chest pain, shortness of breath, swelling in legs), and low blood counts (fatigue, bruising, infection). · Avoid grapefruit and grapefruit juice during treatment as it may increase drug levels. · Inform your doctor if you are pregnant or plan to become pregnant; RYDAPT can harm an unborn baby. · Use effective contraception during treatment and for at least 4 months after the last dose. · Do not breastfeed while taking RYDAPT. · Keep all appointments for regular blood tests and ECG monitoring. |