RYDAPT

Treatment with Rydapt should be initiated by a physician experienced in the use of anti-cancer therapies. Before taking midostaurin, AML patients must have confirmation of FLT3 mutation (internal tandem duplication [ITD] or tyrosine kinase domain [TKD]) using a validated test.

Posology Rydapt should be taken orally twice daily at approximately 12-hour intervals. 2). Prophylactic antiemetics should be administered in accordance with local medical practice as per patient tolerance. AML The recommended dose of Rydapt is 50 mg orally twice daily.

1). In patients receiving a haematopoietic stem cell transplant (SCT), Rydapt should be discontinued 48 hours prior to the conditioning regimen for SCT. Dose modifications in AML Recommendations for dose modifications of Rydapt in patients with AML are provided in Table 1.

Table 1 Rydapt dose interruption, reduction and discontinuation recommendations in patients with AML Phase Criteria Rydapt dosing Grade 3/4 pulmonary infiltrates Interrupt Rydapt for the remainder of the cycle. Resume Rydapt at the same dose when infiltrate resolves to Grade ≤1.

Other Grade 3/4 non-haematological toxicities Interrupt Rydapt until toxicities considered at least possibly related to Rydapt have resolved to Grade ≤2, then resume Rydapt. QTc interval >470 msecs and ≤500 msecs Decrease Rydapt to 50 mg once daily for the remainder of the cycle.

Resume Rydapt at the initial dose in the next cycle provided that QTc interval improves to ≤470 msecs at the start of that cycle. Otherwise continue Rydapt 50 mg once daily. Induction, consolidation and maintenance QTc interval >500 msecs Withhold or interrupt Rydapt for the remainder of the cycle.

If QTc improves to ≤470 msecs just prior to the next cycle, resume Rydapt at the initial dose. If QTc interval is not improved in time to start the next cycle do not administer Rydapt during that cycle. Rydapt may be held for as many cycles as necessary until QTc improves.

0 x 109/l, then resume at 50 mg twice daily. 0 x 109/l) persists >2 weeks and is suspected to be related to Rydapt, discontinue Rydapt. Maintenance only Persistent Grade 1/2 toxicity Persistent Grade 1 or 2 toxicity that patients deem unacceptable may prompt an interruption for as many as 28 days.

ANC:

Summary of the safety profile AML The safety evaluation of Rydapt (50 mg twice daily) in patients with newly diagnosed FLT3-mutated AML is based on a phase III, randomised, double-blind, placebo-controlled study with 717 patients. The overall median duration of exposure was 42 days (range 2 to 576 days) for patients in the Rydapt plus standard chemotherapy arm versus 34 days (range 1 to 465 days) for patients in the placebo plus standard chemotherapy arm.

For the 205 patients (120 in Rydapt arm and 85 in placebo arm) who entered the maintenance phase, the median duration of exposure in maintenance was 11 months for both arms (16 to 520 days for patients in the Rydapt arm and 22 to 381 days in the placebo arm).

5%). 8%). 7%). 9%). Serious ARs occurred at similar rates in patients in the Rydapt versus the placebo arm. The most frequent serious AR in both arms was febrile neutropenia (16%). 3% in the placebo arm. 2%). Safety profile during maintenance phase While Table 3 provides the incidence for ARs over the total duration of the study, when the maintenance phase (single agent Rydapt or placebo) was assessed separately, a difference in the type and severity of ARs was observed.

The overall incidence of ARs during the maintenance phase was generally lower than during the induction and consolidation phase. Incidences of ARs were, however, higher in the Rydapt arm than in the placebo arm during the maintenance phase.

4%). Most of the haematological abnormalities reported occurred during the induction and consolidation phase when the patients received Rydapt or placebo in combination with chemotherapy. 9%). 2% of patients in the Rydapt arm and none in the placebo arm.

ASM, SM-AHN and MCL The safety of Rydapt (100 mg twice daily) as a single agent in patients with ASM, SM-AHN and MCL was evaluated in 142 patients in two single-arm, open-label, multicentre studies. 4 months (range: 0 to 81 months).

8). 5 x 109/l) was generally reversible by withholding Rydapt until recovery and discontinuation in the ASM, SM-AHN and MCL studies. White blood cell counts (WBCs) should be monitored regularly, especially at treatment initiation. 0 x 109/l, as recommended in Tables 1 and 2.

2). Any active serious infection should be under control prior to starting treatment with Rydapt monotherapy. Patients should be monitored for signs and symptoms of infection, including any device-related infections, and if a diagnosis of infection is made appropriate treatment must be instituted promptly, including, as needed, the discontinuation of Rydapt.

Cardiac dysfunction Patients with symptomatic congestive heart failure were excluded from clinical studies. In the ASM, SM-AHN and MCL 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 Rydapt + chemotherapy and placebo + chemotherapy arms. In patients at risk, Rydapt should be used with caution and the patient closely monitored by assessing LVEF when clinically indicated (at baseline and during treatment).

8), however, a mechanistic explanation for this observation was not found. g. due to concomitant medicinal products and/or electrolyte disturbances). Interval assessments of QT by ECG should be considered if Rydapt is taken concurrently with medicinal products that can prolong QT interval.

Pulmonary toxicity Interstitial lung disease (ILD) and pneumonitis, in some cases fatal, have occurred in patients treated with Rydapt monotherapy or in combination with chemotherapy. Patients should be monitored for pulmonary symptoms indicative of ILD or pneumonitis and Rydapt discontinued in patients who experience pulmonary symptoms indicative of ILD or pneumonitis without an infectious aetiology that are ≥Grade 3 (NCI CTCAE).

1. g. rifampicin, St. 5).