Rydapt 25 mg

/ Novartis

The recommended dose of Midostaurin is 50 mg twice daily; it is dosed on days 8 to 21 of induction and consolidation chemotherapy cycles and then twice daily as single-agent maintenance therapy for 12 months.
Dosage for AML
Induction chemotherapy (1 to 2 cycles, 21 days per cycle): On days 8 to 21, 50 mg twice daily.
Consolidation chemotherapy (up to 4 cycles, 21 days per cycle): On days 8 to 21, 50 mg twice daily.
Single-agent maintenance therapy (12 cycles, 28 days per cycle): On days 1 to 28, 50 mg twice daily.
Dose adjustments in AML
Dose interruption, reduction, and discontinuation – recommendations for patients with AM:
During maintenance therapy, Grade 4 neutropenia (ANC <0.5 × 109/liter): Interrupt until ANC(absolute neutrophil count)  ≥1.0 × 109/liter, then resume Midostaurin at 50 mg twice daily.
If neutropenia (ANC <1.0 × 109/liter) persists >2 weeks and is suspected to be related to Midostaurin, discontinue Midostaurin.
Dosing for advanced SM: The recommended starting dose of Midostaurin is 100 mg twice daily. Treatment should be continued as long as clinical benefit is observed or until unacceptable toxicity occurs.
Dose adjustments in advanced SM
Midostaurin dose interruption, reduction, and discontinuation – recommendations for patients with advanced SM:
ANC <1.0 × 109/liter in patients who did not have severe neutropenia at baseline: Interrupt Midostaurin until ANC ≥1.5 × 109/liter, then resume Midostaurin at 50 mg twice daily. If well tolerated, gradually increase to 100 mg twice daily. If ANC <1.0 × 109/liter recurs and is suspected to be related to Midostaurin, discontinue Midostaurin.
Grade 3/4 nausea and/or vomiting despite optimal anti-emetic therapy: Interrupt Midostaurin for 3 days (6 doses), then resume Midostaurin at 50 mg per day and, if well tolerated, gradually increase dose to 100 mg twice daily.
See prescribing information for full details.

Acute myeloid leukaemia (AML): Midostaurin is indicated in combination with standard induction and consolidation chemotherapy followed by single-agent maintenance therapy for adults with newly diagnosed acute myeloid leukaemia (AML) who have an FLT3 mutation.
Advanced systemic mastocytosis (advanced SM): Midostaurin is indicated for the treatment of adult patients with advanced systemic mastocytosis (advanced SM).

Hypersensitivity to the active substance or to any of the excipients.
Concomitant administration of potent CYP3A4 inducers, e.g. rifampicin, St. John’s Wort (Hypericum perforatum), carbamazepine, enzalutamide, phenytoin.

Neutropenia and infections: Neutropenia has occurred in patients receiving Midostaurin as monotherapy and in combination with chemotherapy. Severe neutropenia (ANC <0.5 x 109/l) was generally reversible by withholding Midostaurin until recovery and discontinuation in the advanced SM studies. White blood cell counts (WBCs) should be monitored regularly, especially at treatment initiation.
Cardiac dysfunction: Patients with symptomatic congestive heart failure were excluded from clinical studies. In the advanced SM studies cardiac dysfunction such as congestive heart failure (CHF) (including some fatalities) and transient decreases in left ventricular ejection fraction (LVEF) occurred. In the randomised AML study no difference in CHF was observed between the Midostaurin + chemotherapy and placebo + chemotherapy arms. In patients at risk, Midostaurin should be used with caution and the patient closely monitored by assessing LVEF when clinically indicated (at baseline and during treatment).
Pulmonary toxicity: Interstitial lung disease (ILD) and pneumonitis, in some cases fatal, have occurred in patients treated with Midostaurin monotherapy or in combination with chemotherapy. Patients should be monitored for pulmonary symptoms indicative of ILD or pneumonitis and Midostaurin discontinued in patients who experience pulmonary symptoms indicative of ILD or pneumonitis that are ≥Grade 3 (NCI CTCAE).

Febrile neutropenia, nausea, exfoliative dermatitis,vomiting, headache, petechiae and pyrexia.
See prescribing information for full details.

Enzyme drug-drug interactions
Cytochrome P450 inhibition: Based on in vitro data, midostaurin and its active metabolites, CGP52421 and CGP62221, are considered inhibitors and may potentially cause increases in exposure of co-administered medicinal products primarily cleared by CYP1A2, CYP2D6, CYP2C8, CYP2C9, CYP2E1 and CYP3A4/5. In addition, a time-dependent inhibition of CYP3A4 by midostaurin, CGP52421 and CGP62221 was also observed in vitro.
Cytochrome P450 induction: Based on in vitro data, midostaurin and its active metabolites, CGP52421 and CGP62221, are also considered inducers and may cause decreases in exposure of co-administered medicinal products primarily cleared by CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP3A4/5.
Transporter drug-drug interactions: In vitro experiments demonstrated that midostaurin, CGP52421 and CPG62221 can potentially inhibit P-gp, BCRP, OATP1B1 and BSEP.
See prescribing information for full details

Pregnancy: Midostaurin can cause foetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women.
Lactation: It is unknown whether midostaurin or its active metabolites are excreted in human milk.
See prescribing information for full details.

Reported experience with overdose in humans is very limited. Single doses of up to 600 mg have been given with acceptable acute tolerability. Adverse reactions observed were diarrhea, abdominal pain and vomiting.
There is no known specific antidote for midostaurin. In the event of an overdose, patients must be closely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic and supportive treatment initiated.

Before/after meal: Midostaurin is recommended to be administered with food.