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 patients in complete response followed by Rydapt single agent maintenance therapy, for adult 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 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: CCaution 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

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%): UUpper 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
• Medicinal products with a narrow therapeutic range that are substrates of CYP3A4/5, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, P-gp, BCRP or OATP1B1 should be used with caution when administered concomitantly with midostaurin, and may need dose adjustment to maintain optimal exposure

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