Mutation Testing | RYDAPT® (midostaurin) Capsules

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FLT3 status is key to AML patient care

Identifying patients who are FLT3 mutation-positive may provide both prognostic and selective value, due to the potential of tyrosine kinase inhibition.¹ See below for more information.

Why?

FLT3 is selective

FLT3 positivity (ITD or TKD) is one of the eligibility criteria for treatment with RYDAPT.

When?

At diagnosis

In parallel with cytogenetics. FLT3 test results are needed before day 8 of induction chemotherapy.

Who?

Every patient with newly diagnosed AML

All patients with newly diagnosed AML should receive a FLT3 test (except for those with acute promyelocytic leukaemia).

How?

PCR followed by capillary electrophoresis

The method used during the RATIFY trial can analyse both mutations (ITD and TKD) in parallel.

FLT3 mutation testing to identify patients who are potentially eligible for RYDAPT is performed by The Laboratory of Personalized Molecular Medicine GmbH (Germany), a subsidiary of Invivoscribe Technologies, Inc.

Why test for FLT3?

Prompt FLT3 mutation testing at diagnosis now makes a difference. FLT3 testing significance has changed from prognostic in the past to selective today.

Who should be tested for FLT3?

Diagnostic workup should include comprehensive testing for FLT3-ITD and -TKD mutations, which represent more than 30% of AML cases.^1,4

Patients with ITD and TKD mutations were enrolled in the RATIFY trial and both types of patients benefited from RYDAPT.^5,6

When should the FLT3 test be prescribed?

The European LeukemiaNet (ELN) 2017 recommendations advise testing at diagnosis and obtaining results within 3 days.¹

FLT3 test turnaround time is important to support patient care in the acute setting.

According to the RATIFY phase 3 clinical trial, RYDAPT should be administered in sequential combination with induction chemotherapy starting on day 8 for patients with FLT3 mutations (ITD and/or TKD), irrespective of the cytogenetics findings.⁵

International guidelines recognise the clinical value of a FLT3 test at diagnosis as a selective marker. The latest ELN recommendations (2017) highlight the need for prompt, comprehensive FLT3 testing.¹

How should the FLT3 test be performed?

Multiple methodologies are currently used for FLT3 testing in clinical practice.

The FLT3 test used in the RATIFY clinical trial was based on the Murphy et al and Thiede et al methods and analyses for both ITD and TKD mutations by capillary electrophoresis.^9-11

This approach leads to a more efficient workflow in the lab compared to common methods and could ultimately lead to a faster determination of FLT3 status

The RATIFY clinical trial assay considers that the FLT3 mutation is positive if the mean mutant-to-wild-type signal ratio meets or exceeds the clinical cutoff of 0.05⁹

Patients with a signal ratio less than 0.05 are considered negative for the FLT3 mutation⁹

Download a brochure to learn more about FLT3 testing

AML, acute myeloid leukaemia; BM, bone marrow; FLT3, FMS-like tyrosine kinase 3; ITD, internal tandem duplication; PB, peripheral blood; PCR, polymerase chain reaction; TKD, tyrosine kinase domain.

Learn about RYDAPT efficacy

References: 1. Döhner H, Estey E, Grimwade D, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447. 2. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Acute Myeloid Leukemia V.2.2016. © National Comprehensive Cancer Network, Inc. 2016. All rights reserved. Accessed September 12, 2017. To view the most recent and complete version of the guideline, go online to NCCN.org. 3. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) for Acute Myeloid Leukemia V.3.2017. © National Comprehensive Cancer Network, Inc. 2017. All rights reserved. Accessed September 12, 2017. To view the most recent and complete version of the guideline, go online to NCCN.org. 4. Patel JP, Gönen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079-1089. 5. RYDAPT [Summary of Product Characteristics]. Novartis Pharma AG; 2017. 6. Data on file. Study no. CPKC412A2301. Novartis Pharmaceuticals Corp; 2016. 7. Al-Mawali A, Gillis D, Lewis I. Characteristics and prognosis of adult acute myeloid leukemia with internal tandem duplication in the FLT3 gene. Oman Med J. 2013;28(6):432-440. 8. Santos FP, Jones D, Qiao W, et al. Prognostic value of FLT3 mutations among different cytogenetic subgroups in acute myeloid leukemia. Cancer. 2011;117(10):2145-2155. 9. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation [supplementary appendix published online June 23, 2017]. N Engl J Med. 2017;377(5):454-464. 10. Murphy KM, Levis M, Hafez MJ, et al. Detection of FLT3 internal tandem duplication and D835 mutations by a multiplex polymerase chain reaction and capillary electrophoresis assay. J Mol Diagn. 2003;5(2):96-102. 11. Thiede C, Steudel C, Mohr B, et al. Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood. 2002;99(12):4326-4335.

BASIC SUCCINCT STATEMENT FOR RYDAPT^® (midostaurin) CAPSULES

Important note: Before prescribing, consult full prescribing information of RYDAPT.

Presentation: Soft capsules containing 25 mg of midostaurin.

Indications: Rydapt^® is indicated

in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation chemotherapy, and for adult patients in complete response followed by Rydapt single agent maintenance therapy, for patients with newly diagnosed acute myeloid leukemia (AML) who are FLT3 mutation-positive
as monotherapy for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated haematological neoplasm (SM AHN), or mast cell leukaemia (MCL)

Dosage and administration:

AML Adults: Recommended dose is 50 mg orally twice daily. Rydapt is dosed on days 8 to 21 of induction and consolidation chemotherapy, and then for patients in complete response twice daily as a single agent maintenance until relapse for 12 cycles of 28 days each.

Advanced SM Adults: Recommended dose is 100 mg twice daily.

Dose modifications: Management of adverse drug reactions (ADRs) may require treatment interruption, dose reduction or treatment discontinuation.

Special populations:

Renal impairment: Mild or moderate: no dose adjustment required. Severe or end stage renal disease: No data
Hepatic impairment: Mild or moderate: no dose adjustment required. Severe: No data
Geriatrics (≥65 years): No dose adjustment required. Patients aged ≥60 years: Rydapt should be used only in patients eligible to receive intensive induction chemotherapy with adequate performance status and without significant comorbidities
Pediatrics: Safety and efficacy have not been established

Contraindications: Patients with hypersensitivity to midostaurin or to any of the excipients. Concomitant administration of potent CYP3A4 inducers.

Warnings and precautions:

Neutropenia and infections: Rydapt can cause severe neutropenia. Consider treatment interruption or discontinuation. Monitor White Blood Cell counts regularly and especially at treatment initiation. Delay starting monotherapy with Rydapt until active serious infections have resolved. Observe and promptly manage symptoms of serious infection in patients receiving Rydapt
Cardiac dysfunction: Transient decreases in Left Ventricular Ejection Fraction and Congestive Heart Failure were observed in patients treated with Rydapt in Advanced SM studies. Use Rydapt with caution in patients at risk and monitor patients by assessing LVEF when clinically indicated (at baseline and during treatment). An increased frequency of QTc prolongation was observed in Rydapt-treated patients, without an identified mechanistic explanation. Use Rydapt with caution in patients at risk and consider interval QT assessment by ECG when taken concurrently with medicines that can prolong QT interval
Pulmonary toxicity: Interstitial Lung Disease (ILD) and pneumonitis have been reported during treatment with Rydapt. Monitor patients for severe pulmonary symptoms of ILD or pneumonitis and discontinue Rydapt if patients experience Grade 3 symptoms
Embryo-fetal toxicity and lactation: Rydapt can cause fetal harm. Advise pregnant women of the potential risk to a fetus. Advise women of reproductive potential to use effective contraception during treatment and for at least 4 months after stopping treatment with Rydapt. Women using systemically acting hormonal contraceptives should add a barrier method. Advise nursing women to discontinue breastfeeding during treatment and for at least 4 months after stopping treatment with Rydapt
Severe hepatic impairment: Caution is warranted in patients with severe hepatic impairment and patients should be monitored for toxicity
Severe renal impairment: Caution is warranted in patients with severe renal impairment and patients should be monitored for toxicity
Interactions: Caution is required when concomitantly prescribing with strong inhibitors of CYP3A4
Excipients: Rydapt contains macrogolglycerol hydroxystearate, which may cause stomach discomfort and diarrhoea. Rydapt contains ethanol anhydrous which may be harmful in patients with alcohol related problems, epilepsy or liver problems or during pregnancy or breast feeding

Pregnancy, lactation, females of reproductive potential:

Pregnancy: Rydapt can cause fetal harm. Pregnant women should be advised of the potential risk. Rydapt is not recommended during pregnancy and in women of childbearing potential not using contraception.

Lactation: Breast-feeding should be discontinued during treatment with Rydapt and for at least 4 months after stopping treatment.

Females of reproductive potential:

Pregnancy testing: A pregnancy test is recommended within 7 days prior to starting treatment
Contraception: Sexually active females of reproductive potential should use effective contraception during treatment with Rydapt and for at least 4 months after stopping treatment. Women using systemically acting hormonal contraceptives should add a barrier method of contraception

Infertility: May impair fertility.

Adverse drug reactions:

AML:

Very common (≥10%): Device related infections, febrile neutropenia, petechiae, lymphopenia, hypersensitivity, insomnia, headache, hypotension, epistaxis, laryngeal pain, dyspnoea, nausea, vomiting, stomatitis, abdominal pain upper, haemorrhoids, hyperhidrosis, exfoliative dermatitis, back pain, arthralgia, pyrexia, hyperglycaemia, activated partial thromboplastin time prolonged, absolute neutrophils decreased, haemoglobin decreased, aspartate aminotransferase (AST) increased, alanine aminotransferase (ALT) increased, hypokalaemia, hypernatraemia.

Common (1 to 10%): Upper respiratory tract infection, hyperuricaemia, syncope, tremor, eyelid oedema, hypertension, sinus tachycardia, pericardial effusion, nasopharyngitis, pleural effusion, acute respiratory distress syndrome, anorectal discomfort, abdominal discomfort, dry skin, keratitis, neck pain, bone pain, pain in extremities, catheter-related thrombosis, weight increased, hypercalcaemia.

Uncommon (0.1 to 1%): Neutropenic sepsis.

Advanced SM:

Very common (≥10%): Nausea, vomiting, diarrhea, constipation, peripheral edema, fatigue, pyrexia, urinary tract infection, upper respiratory tract infection, headache, dizziness, dyspnea, cough, pleural effusion, epistaxis, glucose increased, absolute neutrophils decreased, absolute lymphocyte decreased, lipase increased, aspartate aminotransferase (AST) increased, alanine aminotransferase (ALT) increased, total bilirubin increased, amylase increased.

Common (1 to 10%): Hypersensitivity, febrile neutropenia, dyspepsia, gastrointestinal hemorrhage, asthenia, chills, edema, pneumonia, sepsis, bronchitis, oral herpes, cystitis, sinusitis, erysipelas, herpes zoster, contusion, fall, weight increased, disturbance in attention, tremor, vertigo, oropharyngeal pain, hypotension, hematoma.

Uncommon (0.1 to 1%): Anaphylactic shock.

Interactions:

Caution when co-administration of strong CYP3A4 inhibitors including, but not limited to, ketoconazole, ritonavir, clarithromycin and nefazodone as strong CYP3A4 inhibitors may significantly increase exposure to midostaurin especially when (re-)starting midostaurin treatment. Consider alternative therapeutic agent or monitor patient closely for toxicity. Clinical relevance limited
Co-administration of strong CYP3A4 inducers including, but not limited to carbamazepine, rifampin, enzalutamide, phenytoin or St. John's Wort may significantly decrease exposure to midostaurin. Concomitant use of Rydapt with strong CYP3A4 inducers is contraindicated
The PK of midazolam (sensitive CYP34A substrate) was not affected following three dosing days of midostaurin in healthy subjects
Midostaurin and its active metabolites may inhibit P-glycoprotein (P-gp), BCRP, OATP1B1, CYP1A2, CYP2C8, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5; may induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP3A4/5. Medicinal products with a narrow therapeutic range that are substrates of transporters or CYPs should be used with caution when administered concomitantly with midostaurin, and may need dose adjustment to maintain optimal exposure. Midostaurin may inhibit BSEP

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