For:
Advanced Systemic Mastocytosis*
IMPORTANT SAFETY INFORMATION AND INDICATION
Important Safety Information:

CONTRAINDICATIONS
Do not use in patients with hypersensitivity to midostaurin or its excipients. Hypersensitivity reactions have included anaphylactic shock, dyspnea, flushing, chest pain, and angioed…

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Indication: RYDAPT is indicated for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL).

Efficacy

Pivotal Trial Design

RYDAPT(R) (midostaurin) capsules clinical trial design RYDAPT(R) (midostaurin) capsules clinical trial design

*Aggressive systemic mastocytosis (ASM), systemic mastocytosis with an associated hematological neoplasm (SM-AHN), and mast cell leukemia (MCL) are collectively referred to as advanced SM.

  • Patients received RYDAPT 100 mg orally twice daily in 28-day cycles until disease progression or intolerable toxicity1
  • Efficacy was established on the basis of confirmed complete remission (CR) plus incomplete remission (ICR) by six 28-day cycles of oral RYDAPT 100 mg twice daily by modified Valent criteria for ASM and SM-AHN1

Baseline patient characteristics1

  • The study enrolled 116 adult patients with relapse or progression to 0, 1, or 2 prior regimens for SM
    • Among these patients, 36% had prior therapy for SM, and 82% had the KIT D816V mutation detected at baseline
  • The study excluded patients with serum creatinine >2.0 mg/dL, hepatic transaminases >2.5 x ULN or >5 x ULN if disease-related, total bilirubin >1.5 x ULN or >3 x ULN if disease-related, QTc >450 msec, cardiovascular disease including left ventricular ejection fraction <50%, any pulmonary infiltrates, or acute-stage or life-threatening AHN

Based on the pivotal trial, RYDAPT(R) (midostaurin) capsules is the first and only FDA-approved treatment for adult patients with SM-AHN, MCL, or ASM, including those with the KIT D816V mutation(1) Based on the pivotal trial, RYDAPT(R) (midostaurin) capsules is the first and only FDA-approved treatment for adult patients with SM-AHN, MCL, or ASM, including those with the KIT D816V mutation(1)

Response Rates

Measurable reductions in organ damage for adult patients with advanced SM1

Complete remission plus incomplete remission for patients receiving RYDAPT(R) (midostaurin) capsules

aPer study steering committee. Response confirmation after ≥8 weeks was required. No CRs were reported.
bPatients who received concomitant high-dose corticosteroids were considered unevaluable and were excluded from the response assessment.
cAmong patients with response of CR or ICR. The estimated median follow-up for duration of response was 35.4 months overall.
dA + sign indicates a censored value.
e25 patients were not assessable for the presence of MCL on central histopathology review, and 11 patients with unconfirmed presence of an AHN were regarded as not having AHN.

The median duration of treatment was 11 months (range <1-68 months), with treatment ongoing in 17% of patients(1) The median duration of treatment was 11 months (range <1-68 months), with treatment ongoing in 17% of patients(1)

Response rates by mutation status and prior therapy

RYDAPT(R) (midostaurin) capsules response rates by mutation status and prior therapy
  • Major response was defined as the complete resolution of 1 or more clinical finding (measurable organ damage related to mastocytosis)3,4
  • Partial response was defined as a >50% improvement in 1 or more clinical finding (good partial response) or a >20% to ≤50% improvement in 1 or more clinical finding (minor partial response)3,4

Post-hoc Analysis & Supportive Study

Post-hoc exploratory efficacy analysis per modified IWG-MRT-ECNM consensus criteria1

Overall response and duration of response for patients receiving RYDAPT(R) (midostaurin) capsules

aDetermined with 12-week confirmation. Patients who received high-dose corticosteroids were considered evaluable for response.
bMedian DOR was not reached in any subtype. Median follow-up for DOR, among all responders, was 35.0 months.
c31 patients were not assessable for MCL on central review, and 15 patients with unconfirmed AHN were classified as not having AHN.
dMedian exposure to RYDAPT was 11.5 months (range 0.3-68.3 months).

  • Response after 6 cycles of RYDAPT was determined using a computational algorithm. There were 115 patients evaluable for response assessment, of whom 47 (41%) had prior therapy for SM, and 93 (81%) had a documented D816V mutation at baseline1

RYDAPT supportive study1

  • A single-arm, multicenter, open-label, phase 2 study conducted in 26 patients with advanced SM
  • Efficacy was evaluated by the Valent criteria

46% of patients (12 of 26) achieved an overall response in the first 2 cycles of treatment in the RYDAPT(R) (midostaurin) capsules supportive study(1)

DOR, duration of response; ECNM, European Competence Network on Mastocytosis; IWG-MRT, International Working Group-Myeloproliferative Neoplasms Research and Treatment; NE, not estimated; NR, not reached; ULN, upper limit of normal.

Supportive study: a single-arm, multicenter, open-label trial of 26 patients with advanced SM. RYDAPT was administered orally at 100 mg twice daily with food. By Valent criteria per investigator assessment, of 17 patients with SM-AHN, 10 achieved a response (1 partial, 9 major) by 2 cycles that was sustained for at least 8 weeks. Patients who received concomitant corticosteroids were included. Of the 6 patients with MCL, 1 achieved partial response and 1 achieved major response. Median DOR for either group had not been reached, with DOR ranging from 3.4+ to 79.2+ months in patients with SM-AHN and 28.6+ to 32.1+ months in patients with MCL.1

References:
  1. Rydapt [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2018.
  2. Data on file. Study no. PKC412D2201. Novartis Pharmaceuticals Corp; 2016.
  3. Gotlib J, Kluin-Nelemans HC, George TI, et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis. N Engl J Med. 2016;374(26):2530-2541.
  4. Gotlib J, Kluin-Nelemans HC, George TI, et al. Efficacy and safety of midostaurin in advanced systemic mastocytosis [supplementary appendix]. N Engl J Med. 2016;374(26):2530-2541.

INDICATION for RYDAPT® (midostaurin) capsules

Systemic Mastocytosis
RYDAPT is indicated for the treatment of adult patients with aggressive systemic  mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL).

IMPORTANT SAFETY INFORMATION for RYDAPT® (midostaurin) capsules

CONTRAINDICATIONS
  • Do not use in patients with hypersensitivity to midostaurin or its excipients. Hypersensitivity reactions have included anaphylactic shock, dyspnea, flushing, chest pain, and angioedema
WARNINGS AND PRECAUTIONS
Embryofetal Toxicity
  • Do not use during pregnancy. Midostaurin caused severe embryofetal abnormalities and death in animal studies 
  • Verify pregnancy status of females of reproductive potential within 7 days prior to initiating RYDAPT
  • Advise females of reproductive potential to use effective contraception during treatment and for at least 4 months after the last dose
  • Males taking RYDAPT should use effective contraception with females of reproductive potential and pregnant women and for at least 4 months after the last dose
  • Pregnancy exposure registry to monitor pregnancy outcomes: Females who may have been exposed to RYDAPT during pregnancy, directly or through a male partner receiving RYDAPT, should contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 and/or at https://psi.novartis.com
Pulmonary Toxicity
  • Cases of interstitial lung disease and pneumonitis, some fatal, have occurred in patients treated with RYDAPT as monotherapy or with chemotherapy
  • Monitor patients for pulmonary symptoms. Discontinue RYDAPT in patients who experience signs or symptoms of interstitial lung disease or pneumonitis without an infectious etiology
ADDITIONAL CONSIDERATIONS
Lactation
  • Because of the potential for serious adverse reactions in breastfed infants from RYDAPT, advise women not to breastfeed during treatment with RYDAPT and for at least 4 months after the last dose
Infertility
  • Based on findings in animals, RYDAPT may impair fertility in females and males of reproductive potential. It is unknown whether these effects on fertility are reversible
Drug Interactions
  • Strong CYP3A4 Inducers: Avoid concomitant use as strong CYP3A4 inducers decrease exposure to midostaurin and may reduce efficacy
  • Strong CYP3A4 Inhibitors: Coadministration with strong CYP3A4 inhibitors may increase midostaurin concentrations and may increase the risk of toxicity. Monitor patients for increased risk of adverse reactions, especially during the first week of RYDAPT use in each chemotherapy cycle and the first week of consecutive RYDAPT administration. Consider alternative therapies that do not strongly inhibit CYP3A4 activity 
ADVERSE REACTIONS
Aggressive Systemic Mastocytosis (SM), SM With Associated Hematological Neoplasm, Mast Cell Leukemia
  • Most common adverse reactions (≥20%) excluding lab terms were nausea (82%), vomiting (68%), diarrhea (54%), edema (40%), musculoskeletal pain (35%), abdominal pain (34%), fatigue (34%), upper respiratory tract infection (30%), constipation (29%), pyrexia (27%), headache (26%), and dyspnea (23%)
  • Grade ≥3 adverse reactions (≥5%) excluding lab terms were fatigue (9%), sepsis (9%), gastrointestinal hemorrhage (9%), pneumonia (8%), diarrhea (8%), febrile neutropenia (7%), edema (7%), dyspnea (7%), nausea (6%), vomiting (6%), abdominal pain (6%), and renal insufficiency (5%)
  • Most common (≥10%) nonhematologic grade ≥3 lab abnormalities were hyperglycemia (nonfasting) (18%), lipase increase (18%), and hyperuricemia (11%)
  • Most common (≥20%) hematologic grade ≥3 lab abnormalities were thrombocytopenia (27%), neutropenia (22%), anemia (38%) and lymphopenia (27%)

Please see full Prescribing Information for RYDAPT® (midostaurin) capsules.

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