DIQTA 1.0: Drug-Induced QT Prolongation Atlas

RYDAPT

DIR Classification Postmarketing Surveillance Drug Property Information Reference

DIR Classification

Classification:Moderate-DIQT concern

Severity Score:3.0

Description in Drug Labeling: View Full Labeling: SPL in DailyMed | PDF

DOSAGE AND ADMINISTRATION
Recommended Administration
Administer prophylactic anti-emetics before treatment with RYDAPT to reduce the risk of nausea and vomiting.
Administer RYDAPT orally with food, twice daily at approximately 12-hour intervals [see Clinical Pharmacology (12.3)]. Do not open or crush RYDAPT capsules.
If a dose of RYDAPT is missed or vomited, do not make up the dose; take the next dose at the usual scheduled time.
Consider interval assessments of QT by EKG if RYDAPT is taken concurrently with medications that can prolong the QT interval.
ADVERSE REACTIONS
Systemic Mastocytosis
Two single-arm, open-label multicenter trials (Study 2 and Study 3) evaluated the safety of RYDAPT (100 mg twice daily with food) as a single agent in 142 adult patients total with ASM, SM-AHN, or MCL. The median age was 63 (range 24 to 82), 63% had an ECOG performance status of 0 or 1, and 75% had no hepatic impairment (bilirubin and AST ≤ ULN) at baseline. The median duration of exposure to RYDAPT was 11.4 months (range 0 to 81 months), with 34% treated for ≥ 24 months.
The most frequent adverse reactions (≥ 20%), excluding laboratory terms, were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea (Table 4). Grade ≥ 3 adverse reactions reported in ≥ 5%, excluding laboratory terms, were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain, and renal insufficiency (Table 4).
Adverse reactions led to dose modifications (interruption or reduction) in 56% of patients. Among these, the most frequent adverse reactions (> 5%) were gastrointestinal symptoms, QT prolongation, neutropenia, pyrexia, thrombocytopenia, gastrointestinal hemorrhage, lipase increase, and fatigue. The median time to first dose modification for toxicity was 1.6 months, with 75% of dose modifications first occurring within 5 months of starting treatment.
Treatment discontinuation due to adverse reactions occurred in 21% of patients. The most frequent adverse reactions causing treatment discontinuation included infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage.
CLINICAL PHARMACOLOGY
Pharmacodynamics
Cardiac Electrophysiology
The effect of RYDAPT (75 mg twice daily for 3 days) on the QTc interval was evaluated in a randomized, placebo and moxifloxacin controlled, multiple-dose, blinded, parallel study. There was no clinically significant prolongation of QTc interval or relationship between changes in QTc and concentrations for midostaurin and its active metabolites (CGP62221 and CGP52421). The study duration was not long enough to estimate the effects of the metabolite CGP52421 on the QT/QTc interval.
In pooled clinical studies in patients with advanced SM, 4.7% patients had a post-baseline QTcF > 480 ms, no patients had a QTcF > 500 ms, and 6.3% patients had a QTcF > 60 ms compared to baseline.
In a randomized placebo-controlled study in patients with AML, the proportion of patients with QTc prolongation was higher in patients randomized to midostaurin as compared to placebo (QTcF > 480 ms: 10.1% vs 5.7%; QTcF > 500 ms: 6.2% vs 2.6%; QTcF > 60 ms: 18.4% vs 10.7%).

Postmarketing Surveillance

Contingency Table:

Current Drug

Other Drugs

QT Prolongation

24092

Other ADRs

38381587

Odds Ratio = N/A

Drug Property Information

ATC Code(s):

Active Ingredient:MIDOSTAURIN

Active Ingredient UNII:ID912S5VON

Drugbank ID:DB06595

PubChem Compound:9829523

CTD ID:C059539

PharmGKB:

CAS Number:120685-11-2

Dosage Form(s):capsule, liquid filled

Route(s) Of Administrator:oral

Daily Dose:

Chemical Structure:

SMILE Code:
CO[C@@H]1[C@@H](C[C@H]2O[C@]1(C)N1C3=C(C=CC=C3)C3=C1C1=C(C4=C(C=CC=C4)N21)C1=C3CNC1=O)N(C)C(=O)C1=CC=CC=C1

Reference

N/A