Rydapt

Rydapt Adverse Reactions

midostaurin

Manufacturer:

Novartis

Distributor:

Zuellig Pharma
Full Prescribing Info
Adverse Reactions
AML - Summary of the safety profile: The safety evaluation of RYDAPT (50 mg twice daily) in patients with newly diagnosed FLT3 mutated AML is based on a phase III, randomized, double-blind, placebo-controlled study. A total of 717 patients were randomized (1:1) to receive RYDAPT or placebo sequentially (on days 8 to 21) in combination with standard daunorubicin (60 mg/m2 on days 1 to 3) / cytarabine (200 mg/m2 on days 1 to 7) induction and high dose cytarabine (3 g/m2 on days 1, 3, 5) consolidation, followed by maintenance with continuous RYDAPT or placebo treatment according to initial assignment for up to 12 cycles (28 days/cycle). 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).
The most frequent (incidence ≥30%) adverse drug reactions (ADRs) in the RYDAPT plus standard chemotherapy arm were febrile neutropenia, nausea, exfoliative dermatitis, vomiting, headache, petechiae and pyrexia. The most frequent Grade 3/4 ADRs (incidence ≥10%) were febrile neutropenia, lymphopenia, device related infection, exfoliative dermatitis, and nausea.
Serious ADRs occurred in 46.3 % of patients in the RYDAPT plus standard chemotherapy arm versus 51.8 % in the placebo plus standard chemotherapy arm. The most frequent serious ADR in patients in the RYDAPT plus standard chemotherapy arm was febrile neutropenia (15.7%) and this occurred at a similar rate in the placebo arm (15.8%).
Discontinuation due to any adverse event occurred in 9.2% of patients in the RYDAPT arm versus 6.2% in the placebo arm. The most frequent Grade 3/4 adverse event leading to discontinuation in the RYDAPT arm was exfoliative dermatitis (1.2%).
Deaths occurred in 4.3% of patients in the RYDAPT plus standard chemotherapy arm versus 6.3% in the placebo plus standard chemotherapy arm. The most frequent cause of death in the RYDAPT plus standard chemotherapy arm was sepsis (1.2%) and occurred at a similar rate in the placebo arm (1.8%).
Tabulated summary of adverse reactions from clinical trials in AML: Table 6 presents the frequency category of ADRs reported in the phase-III study in patients with newly diagnosed FLT3 mutated AML. ADRs are listed according to MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category using the following convention (CIOMS III) is also provided for each ADR: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Table 7 presents the key laboratory abnormalities from the same phase-III study in patients with newly diagnosed FLT3 mutated AML. (See Tables 6 and 7.)

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Safety profile during maintenance phase: While Table 6 provides the incidence for ADRs 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 ADRs was observed. The overall incidence of ADRs during the maintenance phase was also generally lower. Adverse drug reactions during the maintenance phase with at least ≥5% difference between the RYDAPT and placebo arms were: nausea (46.4% vs 17.9%), hyperglycaemia (20.2% vs 12.5%), vomiting (19% vs 5.4%) and lymphopenia (16.7% vs 8.9%).
Most of the haematological abnormalities reported occurred during the induction and consolidation phase when the patients received RYDAPT or placebo in combination with chemotherapy. The most frequent grade 3/4 haematological abnormalities reported in patients during the maintenance phase with RYDAPT were absolute neutrophil count decrease (20.8% vs 18.9%) and leukopenia (7.5% vs 5.9%).
Overall, ADRs reported during the maintenance phase were of mild to moderate intensity and led to very few discontinuations (1.2% in RYDAPT arm vs 0% in placebo arm).
Description of selected adverse drug reactions: Gastrointestinal disorders: In AML patients during the maintenance phase, low grade nausea and vomiting were observed. These were well managed with supportive prophylactic medication and led to treatment discontinuation in 2 patients, one in each treatment group.
Advanced SM - Summary of the safety profile: The safety of RYDAPT (100 mg twice daily) as a single agent in patients with Advanced SM was evaluated in 142 patients in two single-arm, open-label, multicenter studies. The median duration of exposure to RYDAPT was 11.4 months (range: 0 to 81 months).
The most frequent ADRs (incidence ≥30%) were nausea, vomiting, diarrhoea, peripheral oedema, and fatigue. The most frequent Grade 3/4 ADRs (incidence ≥6%) were fatigue, sepsis, pneumonia, febrile neutropenia, and diarrhoea. The most frequent non-haematologic laboratory abnormalities (incidence ≥30%) were glucose increased, total bilirubin increased, lipase increased, AST increased, and ALT increased while the most frequent haematologic laboratory abnormalities (incidence ≥25%) were absolute lymphocyte decreased and neutrophils decreased. The most frequent Grade 3/4 laboratory abnormalities (incidence ≥10%) were absolute lymphocyte decreased, absolute neutrophils decreased, glucose increased, and lipase increased.
Dose modifications (interruption or adjustment) due to ADRs occurred in 31% of patients. The most frequent ADRs that led to dose modification (incidence ≥5%) were nausea and vomiting.
Adverse events that led to treatment discontinuation occurred in 23.9% of patients. The most common AEs leading to discontinuation were GI related events (5.6%).
Deaths occurred in 18.3% of patients. The most frequent causes of death were disease progression and sepsis.
Tabulated summary of adverse reactions from clinical trials in Advanced SM: Table 8 presents the frequency category of ADRs based on pooled data from two studies in patients with Advanced SM. ADRs are listed according to MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first. In addition, the corresponding frequency category using the following convention (CIOMS III) is also provided for each ADR: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Table 8 presents the key laboratory abnormalities based on pooled data from two studies in patients with Advanced SM. (See Table 8.)

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Table 9 presents the frequency of laboratory abnormalities reported in the Advanced SM trials. (See Table 9.)

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Description of selected adverse drug reactions: Gastrointestinal disorders: In the Advanced SM patient population 17 (12%) patients had a dose adjustment or interruption for nausea, 13 (9.2%) for vomiting, and 7 (4.9%) for diarrhoea. The treatment discontinuation rate was low with 3 (2.1%) patients discontinued for nausea, 2 (1.4%) patients for vomiting, and 1 (0.7%) patient for diarrhoea. Most of the events occurred within the first 6 months of treatment and were well managed with supportive prophylactic medication.
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