| Active Ingredient | MIDOSTAURIN |
|---|
| Drug Name | FDA Application No. | Company | Dosage Form;Route | Strength | RLD Strength | Original Approval or Tentative Approval Date |
Exclusivity Expiration (NCE) |
Exclusivity Expiration (ODE) |
Chemical Type |
Review Classification |
Marketing Status |
TE Code |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| RYDAPT | 207997 | NOVARTIS PHARMS CORP | CAPSULE;ORAL | 25MG | TBD | April 28, 2017 | April 28, 2022 | Apr 28, 2024 | Type 1 - New Molecular Entity | PRIORITY | Prescription | None |
| Parameters | Details |
|---|---|
| Structural Formula |
 |
| Chemical Name | N-[(2S,3R,4R,6R)-3-Methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]-N-methylbenzamide |
| CAS No | 120685-11-2 |
| Molecular Formula | 570.65 g/mole |
| Molecular Weight | C35H30N4O4 |
| Appearance | White to light yellow or light green |
| Solubility | Highly insoluble in aqueous media irrespective of pH but shows increased solubility in less polar alcohols and polar aprotic solvents |
| Water Solubility | <1mg/mL |
| Polymorphism | Polymorphism has been observed for midostaurin and the correct physical form is ensured by the crystallisation process. Since the active substance is dissolved during formulation, physicochemical properties are mostly relevant to the isolation and stability of the active substance. |
| pKa (Strongest Acidic) | 13.45 (Predicted) |
| pKa (Strongest Basic) | -0.83 (Predicted) |
| Log P | 5.89 |
| Identification | IR, XRPD |
| Degradation | Not sensitive to moisture, oxygen and heat up to 100 oC although it does show reversible uptake of a small amount of water. Forced degradation studies in aqueous solution show that midostaurin is inert to acid and base. Minor degradation was observed on exposure to hydrogen peroxide and light |
| Hygroscopic | Slightly hygroscopic |
| Photostability study | Midostaurin is to be protected from exposure to light |
| Melting Point | 235-260 °C |
| BCS Class | II |
| Manufacture of API | Midostaurin is synthesized in two main steps followed by crystallisation and milling. |
| Parameters | Details |
|---|---|
| Indications and Usage | RYDAPT is a kinase inhibitor indicated for the treatment of adult patients with: • Newly diagnosed acute myeloid leukemia (AML) that is FLT3 mutationpositive as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation. Limitations of Use: RYDAPT is not indicated as a single-agent induction therapy for the treatment of patients with AML. • Aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL) |
| Dosage and Administration |
• AML: 50 mg orally twice daily with food. • ASM, SM-AHN, and MCL: 100 mg orally twice daily with food |
| Mechanism of action |
Midostaurin is a small molecule that inhibits multiple receptor tyrosine kinases. In vitro biochemical or cellular assays have shown that midostaurin or its major human active metabolites CGP62221 and CGP52421 inhibit the activity of wild type FLT3, FLT3 mutant kinases (ITD and TKD), KIT (wild type and D816V mutant), PDGFRα/β, VEGFR2, as well as members of the serine/threonine kinase PKC (protein kinase C) family. Midostaurin demonstrated the ability to inhibit FLT3 receptor signaling and cell proliferation, and it induced apoptosis in leukemic cells expressing ITD and TKD mutant FLT3 receptors or overexpressing wild type FLT3 and PDGF receptors. Midostaurin also demonstrated the ability to inhibit KIT signaling, cell proliferation and histamine release and induce apoptosis in mast cells. |
| Absorption |
Midostaurin exhibits time-dependent pharmacokinetics with an initial increase in minimum concentrations (Cmin) that reach the highest Cmin concentrations during the first week followed by a decline to a steady-state after approximately 28 days. The pharmacokinetics of the CGP62221 showed a similar trend. The plasma concentrations of CGP52421 continued to increase after one month of treatment.The highest Cmin and steady-state of midostaurin, CGP62221, and CGP52421 were similar when RYDAPT was administered with food at a dose of 50 mg twice daily or 100 mg twice daily. The time to maximal concentrations (Tmax) occurred between 1 to 3 hours post dose in the fasted state. |
| Food Effect |
Midostaurin exposure, represented by area under the curve over time to infinity (AUCinf), increased 1.2-fold when RYDAPT was coadministered with a standard meal (457 calories, 50 g fat, 21 g proteins, and 18 g carbohydrates) and 1.6-fold when coadministered with a high-fat meal (1007 calories, 66 g fat, 32 g proteins, and 64 g carbohydrates) compared to when RYDAPT was administered in a fasted state. Midostaurin maximum concentrations (Cmax) were reduced by 20% with a standard meal and by 27% with a high-fat meal compared to a fasted state. Tmax was delayed when RYDAPT was administered with a standard meal or a high-fat meal (median Tmax = 2.5 hrs to 3 hrs) |
| Distribution | Midostaurin has an estimated geometric mean volume of distribution (% coefficient of variation) of 95.2 L (31%).Midostaurin and its metabolites are distributed mainly in plasma in vitro. Midostaurin, CGP62221, and CGP52421 are greater than 99.8% bound to plasma protein in vitro. Midostaurin is mainly bound to α1-acid glycoprotein in vitro. |
| Metabolism | Midostaurin is primarily metabolized by CYP3A4. CGP62221 and CGP52421 (mean ± standard deviation) account for 28± 2.7% and 38 ± 6.6% respectively of the total circulating radioactivity. |
| Elimination | The geometric mean terminal half-life (% coefficient of variation) is 21 hours (19%) for midostaurin, 32 hours (31%) for CGP62221 and 482 hours (25%) for CGP52421. Fecal excretion accounted for 95% of the recovered dose with 91% of the recovered dose excreted as metabolites and 4% of the recovered dose as unchanged midostaurin. Only 5% of the recovered dose was found in urine. |
| Peak plasma time (Tmax) | 1 to 3 hours post dose in the fasted state, Fed state: 2.5 hrs to 3 hrs |
| Half life | 21 hours (19%) for midostaurin, 32 hours (31%) for CGP62221 and 482 hours (25%) for CGP52421 |
| Bioavailability | - |
| Age, gender |
Age (20-94 years), sex, race, and mild (total bilirubin greater than 1.0 to 1.5 times the upper limit of normal (ULN) or aspartate aminotransferase (AST) greater than the ULN) or moderate (total bilirubin 1.5 to 3.0 times the ULN and any value for AST) hepatic impairment or renal impairment (creatinine clearance (CLcr) ≥ 30 mL/min) did not have clinically meaningful effects on the pharmacokinetics of midostaurin, CGP62221, or CGP52421. The pharmacokinetics of midostaurin in patients with baseline severe hepatic impairment (total bilirubin greater than 3.0 times the ULN and any value for AST) or severe renal impairment (CLcr 15 to 29 mL/min) is unknown. |
| DMF | Status | Type | Submit Date | Holder |
|---|---|---|---|---|
| Not Available | ||||
| Parameters | Details |
|---|---|
| Strength | 25 MG |
| Excipients used |
Polyoxyl 40 hydrogenated castor oil, gelatin,dehydrated alcohol, corn oil mono-di-triglycerides, titanium dioxide, vitamin E, carmine, hypromellose 2910, propylene glycol |
| Composition of coating material | - |
| Composition of caspule shell | Polyethylene glycol 400, glycerin 85%, ferric oxide yellow, ferric oxide red, purified water |
| Pharmaceutical Development |
Each soft capsule contains approximately 83 mg ethanol anhydrous and 415 mg macrogolglycerol hydroxystearate. Midostaurin is poorly soluble in aqueous media but highly permeable (BCS class II). Initial studies showed midostaurin to be poorly bioavailable when dosed orally. The aim of development therefore was to find a stable dosage form which would allow midostaurin to be delivered orally and in solution so as to be bioavailable without a rate-limiting dissolution step. The active substance is dissolved in a mixture of lipophilic and hydrophilic solvents with a surfactant such that a micro-emulsion is formed spontaneously on addition to aqueous media without it precipitating. The fill solution is encapsulated within a soft gelatin capsule for ease of administration. |
| Manufacture of the product | Preparation of the fill solution; preparation of the gelatin mass; encapsulation followed by washing and drying; imprinting |
| Tablet / Capsule Image |
|
| Appearance | Pale orange oblong soft capsule with red ink imprint ‘PKC NVR’ |
| Imprint code / Engraving / Debossment | Red ink imprint ‘PKC NVR’ |
| Score | No score |
| Color | Pale Orange |
| Shape | Oblong |
| Dimension | 25 mm |
| Mfg by | Novartis Pharma GmbH (EU) |
| Mfg for | - |
| Marketed by | - |
| Distributed by | Novartis Pharmaceuticals Corporation |
| Application No. | Prod No | Patent No | Patent Expiration | Drug Substance Claim | Drug Product Claim | Patent Use Code | Delist Requested | Link |
|---|---|---|---|---|---|---|---|---|
| N207997 | 1 | 7973031 | October 17, 2024 | - | - | U-2007 | - | Download |
| N207997 | 1 | 8222244 | October 29, 2022 | - | - | U-2007 | - | Download |
| N207997 | 1 | 8575146 | December 2, 2030 | - | - | U-2008 | - | Download |
| USP Apparatus | Speed (RPMs) | Medium | Volume (mL) | Recommended Sampling Times (minutes) | Date Updated |
|---|---|---|---|---|---|
| II | 50 | Tier 1:Deionized water with 0.5% Polysorbate 20; Tier 2: Deionized water with 0.5% Polysorbate 20 containing pepsin | 900 | 5, 10, 15, 20, 30 and 45 | November 2, 2017 |
| Label | Link |
|---|---|
| FDA label | Download |
| FDA chemistry review | Download |
| FDA Pharmacology Review(s) | Download |
| FDA Clinical Pharmacology Biopharmaceutics Review(s) | Download |
| FDA BE Recommendation | |
| European Public Assessment Report | Download |
| Territory | Brand name / Generic company name | Link |
|---|---|---|
| EU | RYDAPT | Download |
| UK | - | |
| US | RYDAPT | Download |
| - |
| www.accessdata.fda.gov, www.drugbank.ca, www.ema.europa.eu, www.medicines.org.uk, dailymed.nlm.nih.gov |
