Midostaurin- Rydapt-@- (2017)- Anti-cancer
Drug Name:Midostaurin- Rydapt-@- (2017)- Anti-cancer
List Of Brands:
Indication Type Description:
Drug Interaction
Indication
Adverse Reaction
Contra-Indications
Dosages/ Overdosage Etc
Patient Information
Pharmacology/ Pharmacokinetics
Pregnancy and lactation
Drug Interaction:
DRUG INTERACTIONS
Strong CYP3A4 Inhibitors
Strong CYP3A4 inhibitors may increase exposure to midostaurin and its active
metabolites.
Consider alternative therapies that do not strongly inhibit CYP3A4 or monitor
for increased risk of adverse reactions.
Strong CYP3A4 Inducers:
Avoid concomitant use as strong CYP3A4 inducers decrease exposure to
midostaurin and its active metabolites.
Indication:
U.S. FDA APPROVED DRUGS DURING 2017
Sr.No- 17
Name of the Drug- Rydapt
Active Ingredient- Midostaurin Pharmacological Classification-
To treat multiple acute myeloid leukemia
Date of Approval- 04-28-2017
(Ref- FDA approved List 2017) HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use
RYDAPT safely and effectively. See full prescribing information for
RYDAPT.
RYDAPT® (midostaurin) capsules, for oral use
Initial U.S. Approval: 2017
NDICATIONS AND USAGE
RYDAPT is a kinase inhibitor indicated for the treatment of adult patients
with:
Newly diagnosed acute myeloid leukemia (AML) that is FLT3 mutationpositive
as detected by an FDA-approved test, in combination with standard
cytarabine and daunorubicin induction and cytarabine consolidation.
Adverse Reaction:
ADVERSE REACTIONS
AML:
The most common adverse reactions (. 20%) were febrile neutropenia,
nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain,
epistaxis, device-related infection, hyperglycemia, and upper respiratory
tract infection.
ASM, SM-AHN, or MCL:
The most common adverse reactions (. 20%) were nausea, vomiting, diarrhea,
edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory
tract infection, constipation, pyrexia, headache, and dyspnea.
Contra-Indications:
CONTRAINDICATIONS
Hypersensitivity to midostaurin or any of the excipients
WARNINGS AND PRECAUTIONS
Embryo-fetal Toxicity:
RYDAPT may cause fetal harm when administered to a pregnant woman.
Advise of the potential risk to a fetus.
Pulmonary Toxicity:
Monitor for symptoms of interstitial lung disease or pneumonitis.
Discontinue RYDAPT in patients with signs or symptoms of pulmonary toxicity.
Fatal cases have occurred.
Dosages/ Overdosage Etc:
INDICATIONS AND USAGE
RYDAPT is a kinase inhibitor indicated for the treatment of adult patients
with:
Newly diagnosed acute myeloid leukemia (AML) that is FLT3 mutationpositive
as detected by an FDA-approved test, in combination with standard
cytarabine and daunorubicin induction and cytarabine consolidation.
Limitations of Use:
RYDAPT is not indicated as a single-agent induction therapy for the
treatment of patients with AML.
Aggressive systemic mastocytosis (ASM), systemic mastocytosis with
associated hematological neoplasm (SM-AHN), or mast cell leukemia
(MCL).
DOSAGE AND ADMINISTRATION
AML: 50 mg orally twice daily with food.
ASM, SM-AHN, and MCL: 100 mg orally twice daily with food.
DOSAGE FORMS AND STRENGTHS
Capsules: 25 mg
Patient Information:
PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information).
Pulmonary Adverse Reactions:
Inform patients to seek medical attention for new cough, chest discomfort, or
shortness of breath.
Gastrointestinal Adverse Reactions:
Inform patients that RYDAPT can cause nausea, vomiting, and diarrhea.
Advise patients to contact their healthcare provider if these symptoms
occur or are persisting despite supportive medications
Embryo-Fetal Toxicity
i. Advise pregnant women and females of reproductive potential of the potential
risk to a fetus. Advise females of reproductive potential to use effective
contraception during treatment with RYDAPT and for at least 4 months
after the last dose.
Advise females to inform their healthcare provider of a known or suspected
pregnancy..
ii.. Advise male patients with female partners of reproductive potential to use
effective contraception during treatment with RYDAPT and for 4 months after
the last dose.
Lactation
Advise women not to breastfeed during treatment with RYDAPT and for at least
4 months after the final dose
Infertility
Advise females and males of reproductive potential that RYDAPT may impair
fertility
Distributed by:
Novartis Pharmaceuticals Corporation
East Hanover, New Jersey 07936
Pharmacology/ Pharmacokinetics:
CLINICAL PHARMACOLOGY
1. Mechanism of Action
Midostaurin is a small molecule that 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),
PDGFRÀ, VEGFR2, as well as 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.
2. Pharmacodynamics
Cardiac Electrophysiology
The effect of RYDAPT (75 mg twice daily for 3 days) on the QTc interval was
evaluated in a randomized, placebo and moxifloxacin controlled, multiple-dose,
blinded, parallel study. There was no clinically significant prolongation of QTc
interval or relationship between changes in QTc and concentrations for midostaurin
and its active metabolites (CGP62221 and CGP52421).
3. Pharmacokinetics
Midostaurin exhibits time-dependent pharmacokinetics with an initial increase
in minimum concentrations (Cmin) that reach the highest Cmin concentrations
during the first week followed by a decline to a steady-state after approximately 28
days. The pharmacokinetics of the CGP62221 showed a similar trend.
The time to maximal concentrations (Tmax) occurred between 1 to 3 hours
post dose in the fasted state.
Effect of Food
Midostaurin exposure, represented by area under the curve over time to infinity
(AUCinf), increased 1.2-fold when RYDAPT was coadministered with a standard
meal (457 calories, 50 g fat, 21 g proteins, and 18 g carbohydrates) and
1.6-fold when coadministered with a high-fat meal (1007 calories, 66 g fat,
32 g proteins, and 64 g carbohydrates) compared to when RYDAPT was
administered in a fasted state.
Midostaurin maximum concentrations (Cmax) were reduced by 20% with a
standard meal and by 27% with a high-fat meal compared to a fasted state.
Tmax was delayed when RYDAPT was administered with a standard meal
or a high-fat meal (median Tmax = 2.5 hrs to 3 hrs)
Distribution
Midostaurin has an estimated geometric mean volume of distribution
(% coefficient of variation) of 95.2 L (31%).
Midostaurin and its metabolites are distributed mainly in plasma in vitro.
Midostaurin, CGP62221, and CGP52421 are greater than 99.8% bound to
plasma protein in vitro. Midostaurin is mainly bound to acid glycoprotein in vitro.
Elimination
The geometric mean terminal half-life (% coefficient of variation) is
21 hours (19%) for midostaurin, 32 hours (31%) for CGP62221 and
482 hours (25%) for CGP52421
Metabolism
Midostaurin is primarily metabolized by CYP3A4. CGP62221 and
CGP52421 (mean } standard deviation) account for 28}
2.7% and 38 } 6.6% respectively of the total circulating radioactivity.
Excretion
Fecal excretion accounted for 95% of the recovered dose with 91% of the
recovered dose excreted as metabolites and 4% of the recovered dose as
unchanged midostaurin. Only 5% of the recovered dose was found in urine.
Specific Populations
Age (20-94 years), sex, race, and mild (total bilirubin greater than 1.0 to
1.5 times the upper limit of normal (ULN) or aspartate aminotransferase
(AST) greater than the ULN) or moderate (total bilirubin 1.5 to 3.0 times
the ULN and any value for AST) hepatic impairment or renal impairment
(creatinine clearance (CLcr) . 30 mL/min) did not have clinically
meaningful effects on the pharmacokinetics of midostaurin, CGP62221,
or CGP52421.
The pharmacokinetics of midostaurin in patients with baseline severe hepatic
impairment (total bilirubin greater than 3.0 times the ULN and any value for AST)
or severe renal impairment (CLcr 15 to 29 mL/min) is unknown.
Pregnancy and lactation:
USE IN SPECIFIC POPULATIONS
1. Pregnancy
Risk Summary
Based on mechanism of action and findings in animal reproduction studies,
RYDAPT may cause fetal harm when administered to a pregnant woman .
There are no available data on RYDAPT use in pregnant women to inform
a drug-associated risk of major birth defects and miscarriage.
In animal reproduction studies, oral administration of midostaurin 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..
Advise pregnant women of the potential risk to a fetus.
The background risk of major birth defects and miscarriage for the indicated
population are unknown. Adverse outcomes in pregnancy occur regardless of the
health of the mother or the use of medications.
In the U.S. general population, the estimated background risk of major birth
defects and miscarriage in clinically recognized pregnancies is 2% to 4% and
15% to 20%, respectively.
2. Lactation
Risk Summary
There are no data on the presence of midostaurin or its active metabolites in
human milk, the effect on the breastfed infant, or the effect on milk production.
Orally administered midostaurin and its active metabolites pass into the milk of
lactating rats within 1 hour of a 30 mg/kg/day dose, with approximately 5 times
more in the milk of lactating rats compared to plasma.
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.
3. Females and Males of Reproductive Potential
Pregnancy Testing
Pregnancy testing is recommended for females of reproductive potential within
seven days prior to initiating RYDAPT.
Contraception
Females
RYDAPT may cause fetal harm when administered to a pregnant woman
Advise females of reproductive potential to use effective contraception during
treatment with RYDAPT and for 4 months after the last dose.
Males
Males with female sexual partners of reproductive potential should use effective
contraception during RYDAPT treatment and for at least 4 months after stopping
treatment with RYDAPT
Infertility
Based on findings in animals, RYDAPT may impair fertility in females and males
of reproductive potential. It is not known whether these effects on fertility are
reversible
4. Pediatric Use
Safety and effectiveness of RYDAPT have not been established in pediatric
patients.
5. Geriatric Use
Of the 142 patients with advanced SM in clinical studies of RYDAPT, 64 (45%)
were aged 65 and over, and 16 (11%) were aged 75 years and over.
No overall differences in safety or response rate were observed between
the subjects aged 65 and over compared with younger subjects.
Greater sensitivity of older individuals cannot be ruled out.
Clinical studies in AML with RYDAPT did not include sufficient numbers of
subjects aged 65 and over to determine whether they respond differently
from younger subjects.
In general, administration for elderly patients should be cautious, based on
patient’s eligibility for concomitant chemotherapy and reflecting the greater
frequency of concomitant disease or other drug therapy.
