Midostaurin

Midostaurin is used for: Acute Myeloid Leukemia (AML),

Take with food twice daily at ~12-hr intervals Administer prophylactic antiemetics before treatment to reduce the risk of nausea and vomiting

Hypersensitivity; reactions have included anaphylactic shock, dyspnea, flushing, chest pain, and angioedema (eg, swelling of the airways or tongue, with or without respiratory impairment)

Cases of interstitial lung disease and pneumonitis, some fatal, reported with monotherapy or in combination with chemotherapy; monitor for pulmonary symptoms; discontinue if signs or symptoms of interstitial lung disease or pneumonitis occur without an infectious etiology Based on its mechanism of action and findings from animal reproduction studies, midostaurin may cause fetal harm when administered to pregnant women

Pregnancy Based on mechanism of action and findings in animal reproduction studies, may cause fetal harm when administered to pregnant women Administration to pregnant rats and rabbits during organogenesis caused embryo-fetal toxicities, including late embryo-fetal death and reduced fetal birth weight, with delays in fetal growth at doses lower than the recommended human dose Pregnancy testing: Recommended for females of reproductive potential within 7 days before initiating midostaurin Infertility: Based on findings in animals, midostaurin may impair fertility in females and males of reproductive potential Contraception Females: Drug may cause fetal harm when administered to a pregnant woman; advise females of reproductive potential to use effective contraception during treatment and for 4 months after the last dose Males: Males with female sexual partners of reproductive potential should use effective contraception during treatment and for at least 4 months after the last dose Lactation Unknown if distributed in human breast milk Orally administered midostaurin and its active metabolites pass into the milk of lactating rats within 1 hr of a 30-mg/kg/day dose, with approximately 5 times more in the milk of lactating rats compared with plasma Because of the potential for serious adverse reactions in breastfed infants, advise women not to breastfeed during treatment and for at least 4 months after the last dose

Side effects of Midostaurin : >10% (AML) Nausea (83%) Febrile neutropenia (83%) Hypocalcemia (74%) Increased ALT, all grades (71%) Mucositis (66%) Vomiting (61%) Headache (46%) Petechiae (36%) Musculoskeletal pain (33%) Epistaxis (28%) Device-related infection (24%) Hypernatremia (21%) Upper respiratory tract infection (20%) Hyperglycemia (20%) Increased ALT, grades 3 and 4 (20%) Hemorrhoids (15%) Arthralgia (14%) Hyperhidrosis (14%) Prolonged aPTT (13%) Renal insufficiency (12%) Insomnia (12%) >10% (SM) Nausea (82%) Hyperglycemia (80%) Vomiting (68%) Lymphopenia (66%) Leukopenia (61%) Anemia (60%) Diarrhea (54%) Thrombocytopenia (50%) Neutropenia (49%) Edema (40%) Increased alkaline phosphatase (39%) Hypocalcemia (39%) Lipase increased (37%) Hyperuricemia (37%) Increased GGT (35%) Musculoskeletal pain (35%) Hyponatremia (34%) Increased AST (32%) Increased ALT (31%) Fatigue (34%) Abdominal pain (34%) Upper respiratory tract infection (30%) Hyperbilirubinemia (29%) Hypoalbuminemia (27%) Pyrexia (27%) Constipation (29%) Headache (26%) Hypokalemia (25%) Increased creatinine (25%) Hyperkalemia (23%) Dyspnea (23%) Hypophosphatemia (22%) Increased amylase (20%) Hypomagnesemia (20%) Arthralgia (19%) Cough (18%) Urinary tract infection (16%) GI hemorrhage (14%) Rash (14%) Dizziness (13%) Pleural effusion (13%) Epistaxis (12%) QT prolonged (11%) Insomnia (11%) Renal insufficiency (11%) 1-10% (AML) Hyperuricemia (8%) Hypertension (8%) Cellulitis (7%) Fungal infection (7%) Dry skin (7%) Weight increased (7%) Pleural effusion (6%) Thrombosis (5%) Tremor (4%) Pericardial effusion (4%) Hypercalcemia (3%) Eyelid edema (3%) 1-10% (SM) Pneumonia (10%) Herpes virus infection (10%) Sepsis (9%) Hypotension (9%) Febrile neutropenia (8%) Disturbance in attention (7%) Tremor (6%) Hematoma (6%) Cardiac failure (6%) Bronchitis (6%) Dyspepsia (6%) Weight increased (6%) Contusion (6%) Cellulitis or erysipelas (5%) Vertigo (5%) Chills (5%) Oropharyngeal pain (4%) Myocardial infarction or ischemia (4%) Hypersensitivity (4%) Mental status changes (4%) Pulmonary edema (3%) Gastritis (3%) Interstitial lung disease or pneumonitis (2%)

Inhibits multiple receptor tyrosine kinases In vitro biochemical or cellular assays have shown that midostaurin or its major human active metabolites CGP62221 and CGP52421 inhibit the activity of wild type FLT3, FLT3 mutant kinases (ITD and TKD), KIT (wild type and D816V mutant), PDGFR-alpha/beta, VEGFR2, and members of the serine/threonine kinase PKC (protein kinase C) family Midostaurin demonstrated the ability to inhibit FLT3 receptor signaling and cell proliferation, and it induced apoptosis in leukemic cells expressing ITD and TKD mutant FLT3 receptors or overexpressing wild type FLT3 and PDGF receptors Midostaurin also demonstrated the ability to inhibit KIT signaling, cell proliferation, and histamine release and induce apoptosis in mast cells