Rydapt

Rydapt

midostaurin

Manufacturer:

Novartis

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Midostaurin.
Description
Each capsule contains 25 mg of midostaurin.
Excipients/Inactive Ingredients: Macrogolglycerol hydroxystearate/polyoxyl 40 hydrogenated castor oil, gelatin, macrogol 400/polyethylene glycol 400, glycerol, ethanol anhydrous/dehydrated alcohol, corn oil mono-di-triglycerides, titanium dioxide (E171), all-rac-alpha-tocopherol/Vitamin E, iron oxide yellow/ferric oxide (E172), iron oxide red/ferric oxide (E172), carmine (E120), hypromellose 2910, propylene glycol, purified water.
Action
Pharmacology: Pharmacodynamics: Two major metabolites have been identified in murine models and humans.
In proliferation assays with FLT3-ITD expressing cells, CGP62221 showed similar potency compared to the parent compound, whereas CGP52421 was approximately 10 fold less potent.
Cardiac Electrophysiology: A dedicated QT study in 192 healthy subjects with a dose of 75mg twice daily did not reveal clinically significant prolongation of QT by midostaurin and CGP62221 and the study duration was not long enough to estimate the QTc prolongation effects of the long-acting metabolite CGP52421. Therefore, the change from baseline in QTcF with the concentration of midostaurin and both metabolites was further explored in a phase II study in 116 patients with Advanced SM. At the median peak Cmin concentrations attained at a dose of 100 mg twice daily, neither midostaurin, CGP62221 nor CGP52421 showed a potential to cause clinically significant QTcF prolongation, since the upper bounds of predicted change at these concentration levels were less than 10msecs with 6.3, 2.4, and 4.7 msecs, respectively.
Mechanism of Action:
Midostaurin inhibits multiple receptor tyrosine kinases, including FLT3 and KIT kinase. Midostaurin inhibits FLT3 receptor signaling and induces cell cycle arrest and apoptosis in leukemic cells expressing ITD and TKD mutant receptors or overexpressing wild type receptors. Midostaurin inhibits both the wild type and D816V mutant KIT, leading to interference with the aberrant signaling of KIT and inhibits mast cell proliferation and survival, and histamine release.
In addition, it inhibits several other receptor tyrosine kinanses such as FGFR or VEGFR2, as well as members of the serine/threonine kinase family PKC (protein kinase C). Midostaurin binds to the catalytic domain of these kinases and inhibits the mitogenic signaling of the respective growth factors in cells, resulting in growth arrest.
Midostaurin in combination with many chemotherapeutic agents (with the exception of methotrexate) resulted in synergistic growth inhibition in FLT3-ITD expressing AML cell lines.
Clinical Studies: Acute Myeloid Leukemia (AML): The efficacy and safety of RYDAPT in combination with standard chemotherapy versus placebo plus standard chemotherapy and as single agent maintenance therapy was investigated in 717 patients (18 to 60 years of age) in a randomized, double-blind, phase III study. Patients with newly diagnosed FLT3 mutated AML as determined by a clinical trial assay were randomized (1:1) to receive RYDAPT 50 mg twice daily (n=360) or placebo (n=357) sequentially in combination with standard daunorubicin (60 mg/m2 daily on days 1 to 3) / cytarabine (200 mg/m2 daily on days 1 to 7) induction and high dose cytarabine (3 g/m2 every 12 hours on days 1, 3, 5) consolidation, followed by continuous RYDAPT or placebo treatment according to initial assignment for up to 12 additional cycles (28 days/cycle). While the study included patients with various AML related cytogenetic abnormalities, patients with acute promyelocytic leukemia (M3) or therapy related AML were excluded. Patients were stratified by FLT3 mutation status: TKD, ITD with allelic ratio <0.7, and ITD with allelic ratio ≥0.7.
The two treatment groups were generally balanced with respect to the baseline demographics of disease characteristics and details are shown in Table 1. (see Table 1.)

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Patients who proceeded to hematopoietic stem cell transplant (SCT) stopped receiving study treatment on or before the time of stem cell infusion. The overall rate of SCT was 59.4% (214/360) of patient in the RYDAPT plus standard chemotherapy arm versus. 55.2% (197/357) in the placebo plus standard chemotherapy arm. All patients were followed for survival.
The primary endpoint of the study was overall survival (OS), measured from the date of randomization until death by any cause. The primary analysis was conducted after a minimum follow-up of approximately 3.5 years after the randomization of the last patient. The study demonstrated a statistically significant improvement in OS with a 23% risk reduction of death for RYDAPT plus standard chemotherapy over placebo plus standard chemotherapy (see Table 2 and Figure 1).

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The key secondary endpoint was event free survival (EFS; an EFS event is defined as a failure to obtain a complete remission (CR) within 60 days of initiation of protocol therapy, or relapse, or death from any cause). The EFS showed a statistically significant improvement for RYDAPT plus standard chemotherapy over placebo plus standard chemotherapy (see Table 2 and Figure 2).

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Sensitivity analyses for both OS and EFS when censored at the time of SCT also supported the clinical benefit with RYDAPT plus standard chemotherapy over placebo. There was a trend favoring RYDAPT for CR rate by day 60 for the midostaurin arm (58.9% versus 53.5%; P = 0.073) that continued when considering all CRs during induction (65.0% versus 58.0%; P = 0.027). In addition, in patients who achieved complete remission in induction, the cumulative incidence of relapse (CIR) at 12 months was 26% in the midostaurin arm vs. 41% in the placebo arm. (See Table 2.)

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Advanced Systemic Mastocytosis (ASM): The efficacy of RYDAPT in patients with aggressive systemic mastocytosis (ASM) or mast cell leukemia (MCL), with or without an associated hematologic non-mast cell lineage disorder (AHNMD), collectively referred to as Advanced SM, were evaluated in two open-label, single-arm, multicenter studies (142 patients in total).
The pivotal study was a multicenter, single-arm phase II study in 116 patients with Advanced SM (Study CPKC412D2201). RYDAPT was administered orally at 100 mg twice daily until disease progression or intolerable toxicity. Of the 116 patients enrolled, 89 were considered eligible for response assessment and constituted the primary efficacy population (PEP). Of these, 73 patients had ASM (57 with an AHNMD), and 16 patients had MCL (6 with an AHNMD). The median age in the PEP was 64 years with approximately half of the patients to ≥ 65 years). Approximately one-third (36%) received prior anti-neoplastic therapy for Advanced SM. At baseline in the PEP, 65% of the patients had >1 measurable C-finding. The KIT D816V mutation was detected in 82% of patients.
The primary endpoint was overall response rate (ORR). Response rates were assessed based on the modified Valent and Cheson criteria and responses were adjudicated by a study steering committee. Secondary endpoints included duration of response, time to response, and overall survival. Responses to RYDAPT are shown in Table 3. Activity was observed regardless of KIT D816V status, number of prior therapies, and presence or absence of an AHNMD. Forty-six percent of patients had a decrease in bone marrow infiltration exceeded 50% and 58% had a decrease in serum tryptase levels exceeded 50%. Spleen volume decreased by ≥10% in 68.9% of patients with at least 1 post-baseline assessment (26.7% of patients had a reduction of ≥35%, which correlates with a 50% decrease by palpation).
The median time to response was 0.3 months (range: 0.1 to 3.7 months). The median duration of follow-up was 43 months. (See Table 3.)

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Patient-reported outcome assessments were evaluated using the Memorial Symptom Assessment Scale (MSAS) and SF-12 questionnaires. The most commonly reported baseline symptoms (> 65% of prevalence) on the MSAS were "lack of energy", "feeling drowsy", and "difficulty sleeping". The prevalence of all symptoms had decreased at Cycle 12, with the exception of nausea and vomiting. Maximum improvement was reported for the symptom "weight loss", where the prevalence decreased from 50% to 17%. A similar pattern of improvements was seen at Cycle 6, and for best TMSAS score during the study. Overall, responders showed more improvement than non-responders with no worsening of any symptoms. For the SF-12 physical component score, best mean score at baseline were below those reported for a healthy population, whereas best mean scores reported during the study approached those reported for a healthy population, especially in responders. A similar trend was observed for the SF-12 mental component scale.
The supportive study was a single arm, multicenter, open-label phase II study of 26 patients with Advanced SM (CPKC412A2213). RYDAPT was administered orally at 100 mg twice daily. Lack of a major response (MR) or partial response (PR) by the end of the second cycle required in discontinuation from the study treatment. Twenty (76.9%) patients had ASM (17 [85%] with AHNMD) and 6 patients (23.1%) had MCL (2 [33.3%] with AHNMD). The median age was 64.5 years with half of the patients ≥ 65 years. At baseline, 88.5% had > 1 C-finding and 69.2% had received at least one prior anti-neoplastic regimen.
The primary endpoint was ORR evaluated by the Valent criteria during the first two cycles of treatment. Nineteen patients (73.1%; 95% CI = [52.2, 88.4]) achieved a response during the first two cycles of treatment (13 MR; 6 PR). The median duration of follow-up was 73 months, and the median duration of response has not been reached. Median overall survival was 40.0 months (patients were only followed for up one year after treatment discontinuation for survival).
Pharmacokinetics: Absorption: In humans, the absorption of midostaurin is rapid after oral administration, with Tmax of total radioactivity observed at 1 to 3 hours post dose. In healthy subjects, the extent of midostaurin absorption (AUC) was increased by an average of 22% when RYDAPT was co-administered with a standard meal, and by an average of 59% when co-administered with a high-fat meal. Peak midostaurin concentration (Cmax) was reduced by 20% with a standard meal and by 27% with a high-fat meal versus on an empty stomach. Time to peak concentration were also delayed in presence of a standard meal or a high-fat meal (median Tmax = 2.5 hrs to 3 hrs). In clinical studies, midostaurin was administered with a light meal, in order to decrease potential nausea and vomiting events and it is recommended that midostaurin is administered to patients with food.
Distribution: Midostaurin has a high tissue distribution of geometric mean Vz/F= 95.2 L. Midostaurin and its metabolites are distributed mainly in plasma rather than red blood cells. In vitro data showed midostaurin is greater than 98% bound to plasma protein mainly to alpha-1-acid glycoprotein (AGP).
Biotransformation/metabolism: Midostaurin is metabolized by CYP3A4 mainly via oxidative pathways and the major plasma components included midostaurin and two major active metabolites; CGP62221 and CGP52421 accounting for 27.7± 2.7% and 37.97± 6.6% respectively of the total plasma exposure.
Elimination: The median terminal half-lives of midostaurin, CGP62221 and CGP52421 in plasma are approximately 20.5, 32.3 and 471 hours. The Human Mass Balance study results indicate that fecal excretion is the major route of excretion (78% of the dose), and mostly as metabolites (73% of the dose) while unchanged midostaurin accounts for 3% of the dose. Only 4% of the dose is recovered in urine.
Linearity/Non-Linearity: In general, midostaurin and its metabolites showed no major deviation from dose-proportionality after a single dose in the range of 25 mg to 100 mg. However, there was a less than dose-proportional increase in exposure after multiple doses within the dose range of 50 mg to 225 mg daily.
Following multiple oral doses, midostaurin displayed time-dependent pharmacokinetics with an initial increase in plasma concentrations during the first week (peak Cmin) followed by a decline with time to a steady-state after approximately 28 days. While the exact mechanism for the declining concentration of midostaurin is unclear, it may be possibly due to CYP3A4 enzyme auto-induction. The pharmacokinetics of the CGP62221 metabolite showed a similar trend. However, CGP52421 concentrations increased up to 2.5 fold with Advanced SM to and up to 9-fold for AML, compared to midostaurin after one month of treatment.
In vitro evaluation of drug interaction potential: Enzyme drug-drug interactions: Cytochrome P450 inhibition: Based on in-vitro data, midostaurin and its active metabolites, CGP52421 and CGP62221, are considered as inhibitors and may potentially cause increases in exposure of co-administered medicinal products primarily cleared by certain CYPs. Therefore, medicinal products with a narrow therapeutic range that are substrates of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 should be used with caution when administered concomitantly with midostaurin, and may need dose adjustment to maintain optimal exposure.
Cytochrome P450 induction: Based on in-vitro data, midostaurin and its active metabolites, CGP52421 and CGP62221, are also considered inducers and may cause decreases in exposure of co-administered medicinal products primarily cleared by certain CYPs. Therefore, medicinal products with a narrow therapeutic range that are substrates of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, and CYP3A should be used with caution when administered concomitantly with midostaurin, and may need dose adjustment to maintain optimal exposure.
Transporter drug-drug interactions: Based on in-vitro data, midostaurin may cause relevant increases in the exposure of drugs or substances known to be substrates of OATP1B1 Therefore, medicinal products with a narrow therapeutic range that are substrates of OATP1B1 should be used with caution when administered concomitantly with midostaurin, and may need dose adjustment to maintain optimal exposure.
Special populations: Pediatric patients (below 18 years): There are limited data in pediatric patients and the safety and efficacy of RYDAPT in this population has not been established. The pharmacokinetics of midostaurin in pediatric patients were explored in phase 1 dose escalation monotherapy study with 22 patients (ages 3 months to 18 years of age) with AML or MLL-rearranged ALL using a population PK approach. After adjusting for body weight, exposures of midostaurin and its two metabolites in pediatrics fell within the ranges predicted by modeling data from adults.
Geriatric patients (65 years or above): Based on population PK model analyses of the effect of age on clearance of midostaurin and its active metabolites, there was no statistically significant finding and the anticipated changes in exposure were not deemed to be clinically relevant. In adult patients with Advanced SM or AML, no midostaurin dose adjustment is required based on age.
Gender: Based on population PK model analyses of the effect of gender on clearance of midostaurin and its active metabolites, there was no statistically significant finding and the anticipated changes in exposure were not deemed to be clinically relevant. No midostaurin dose adjustment is required based on gender.
Race/Ethnicity: There are no differences in the pharmacokinetic profile between Caucasian and Black subjects. Based on the phase 1 study in healthy Japanese volunteers, pharmacokinetic profiles of midostaurin and its metabolites (CGP62221 and CGP52421) are similar compared to those observed in other PK studies conducted in Caucasians and Blacks. No midostaurin dose adjustment is required based on ethnicity.
Patients with hepatic impairment: A dedicated hepatic impairment study assessed the systemic exposure of midostaurin in subjects with baseline mild or moderate hepatic impairment (Child-Pugh Class A or B, respectively) and control subjects with normal hepatic function. There was no clinically relevant increase in exposure (AUC) to plasma midostaurin in subjects with mild or moderate hepatic impairment compared to subjects with normal hepatic function. No dosage adjustment is necessary for patients with baseline mild or moderate hepatic impairment. The pharmacokinetics of midostaurin have not been assessed in patients with baseline severe hepatic impairment (Child-Pugh Class C).
Patients with renal impairment: No dedicated renal impairment study was conducted for midostaurin. Population pharmacokinetic (popPK) analyses were conducted using data from clinical trials in patients with AML (n=180) and Advanced SM (n=141). Out of the 321 patients included, 177 patients showed pre-existing mild (n=113), moderate (n=60) or severe (n=4) renal impairment (15 mL/min ≤creatinine clearance [CrCL] <90 mL/min). 144 patients showed normal renal function (CrCL>90 mL/min) at baseline. Based on the population PK analyses, midostaurin clearance was not significantly impacted by renal impairment and therefore, no dosage adjustment is necessary for patients with mild or moderate renal impairment.
Toxicology: Non-clinical Safety Data: Midostaurin has been evaluated in safety pharmacology, single/repeated dose toxicity, genotoxicity, reproductive and developmental toxicity studies.
Safety pharmacology and single/repeat dose toxicity: Safety pharmacology studies indicate that midostaurin is unlikely to interfere with vital functions of the central nervous systems. In vitro, midostaurin did not inhibit hERG channel activity up to the limit of solubility of 12 microM. The two major human metabolites GGP52421 and CGP6221 (also tested up to the limit of solubility) inhibited hERG current by 38.5% at 1.5 microM and 11.3% at 1.21 microM respectively. Midostaurin and the two metabolites are highly protein bound and the free concentrations at therapeutic doses are far below the concentrations associated with no/minimal hERG inhibition in vitro. The risk of hERG related-QT prolongation appears to be low. In the repeat dose studies in dogs, a decrease in heart rate and a prolongation of the P-Q interval was seen in individual animals at 10 and 30 mg/kg; there were no morphological changes in the heart.
In the repeat dose studies, the key target organs identified were the gastrointestinal tract (emesis in dogs and monkeys, diarrhea and mucosal alteration), testes (decreased spermatogenesis), bone marrow (hypocellularity) and lymphoid organs (depletion/atrophy). The effect on the bone marrow and lymphoid organs was accompanied by hematological changes of decreased white blood cells, lymphocytes and erythrocytic parameters. An increase in liver enzymes (ALT and AST) was seen consistently in rats, and in dogs and monkeys in long term studies of ≥3 months duration. There were no corresponding pathological changes in the liver. Inhibition of spermatogenesis was seen in dogs at doses ≥ 3 mg/kg. The no-adverse-effect level after 12 months of treatment was 1 mg/kg in dogs and 3 mg/kg in rats.
Reproductive toxicity: See Use in Pregnancy & Lactation and Precautions.
Genotoxicity: In vitro and in vivo genotoxicity studies covering relevant genotoxicity endpoints showed no evidence of mutagenic or clastogenic activity. No carcinogenicity studies have been performed.
Indications/Uses
RYDAPT is indicated: in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation chemotherapy, and for patients in complete response followed by Rydapt single agent maintenance therapy, for adult patients with newly diagnosed acute myeloid leukaemia (AML) who are FLT3 mutation-positive.
For the treatment of adult patients with advanced systemic mastocytosis (Advanced SM).
Dosage/Direction for Use
Treatment with RYDAPT should be initiated by a physician experienced in the use of anticancer therapies.
Dosage regimen: Target population: Recommended dose in AML: The recommended dose of RYDAPT is 50 mg twice daily. RYDAPT is dosed on days 8-21 of induction and consolidation chemotherapy cycles and then twice daily as single agent maintenance for 12 months.
Recommended dose in Advanced SM: The recommended starting dose of RYDAPT is 100 mg twice daily.
Treatment should be continued as long as clinical benefit is observed or until unacceptable toxicity occurs.
Dose modifications: Dose modifications in AML: Recommendations for dose modifications of RYDAPT in patients with AML are provided in Table 4. (See Table 4.)

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Dose modifications in Advanced SM: Recommendations for dose modifications of RYDAPT in patients with Advanced SM are provided in Table 5. (See Table 5.)

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Special populations: Renal impairment: No dose adjustment is required for patients with mild or moderate renal impairment. Clinical experience in patients with severe renal impairment is limited. No data are available in patients with end-stage renal disease (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: No dose adjustment is required in patients with mild or moderate (Child-Pugh A or B) hepatic impairment. No study has been completed in patients with severe (Child-Pugh C) hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Pediatric patients (below 18 years): The safety and efficacy of RYDAPT in pediatric patients (0 to less than 18 years) have not been established (see Pharmacology: Pharmacokinetics under Actions).
Geriatric patients (65 years or above): No dosage regimen adjustment is required in patients over 65 years of age (see Pharmacology: Pharmacokinetics under Actions).
Method of administration: RYDAPT should be taken orally, twice daily at approximately 12 hour intervals. RYDAPT should be taken with food to help prevent nausea (see Pharmacology: Pharmacokinetics under Actions).
Prophylactic anti-emetics should be administered in accordance with local medical practice as per patient tolerance.
RYDAPT capsules should be swallowed whole with a glass of water. RYDAPT capsules should not be opened, crushed or chewed.
If a dose is missed, the dose should not be made up and the patient should only take the next scheduled dose at the scheduled time.
If vomiting occurs, the patient should not take an additional dose of RYDAPT, but should take the next scheduled dose.
Overdosage
Reported experience with overdose in humans is very limited. Single doses of up to 600 mg have been given with acceptable acute tolerability.
General supportive measures should be initiated in all cases of overdose.
Contraindications
RYDAPT is contraindicated in patients with hypersensitivity to midostaurin or to any of the excipients.
Special Precautions
Neutropenia/Infections: Neutropenia has occurred in patients receiving RYDAPT as monotherapy and in combination with chemotherapy (see Adverse Reactions). Severe neutropenia (ANC less than 0.5 x 109/L) was generally reversible by withholding RYDAPT until recovery or discontinuation in the Advanced SM studies. White blood cells (WBCs) should be monitored regularly, especially at treatment initiation.
In patients who develop unexplained severe neutropenia, treatment with RYDAPT should be interrupted until ANC is greater than or equal to 1.0 x 109/L in patients with AML or 1.5 x 109/L in patients with Advanced SM, as recommended in Tables 4 and 5. RYDAPT should be discontinued in patients who develop recurrent or prolonged severe neutropenia that is suspected to be related to RYDAPT (see Dosage & Administration).
Any active serious infections should be under control prior to starting treatment with RYDAPT monotherapy. Patients should be monitored for signs and symptoms of infection and if a diagnosis of infection is made, appropriate treatment should be instituted promptly, including as needed, the discontinuation of RYDAPT.
Cardiac dysfunction: In the Advanced SM studies with RYDAPT, cardiac dysfunction such as congestive heart failure (CHF), some of which were fatal, and transient decreases in left ventricular ejection fraction (LVEF) occurred. Fatal cardiac failure was reported in patients in the Advanced SM studies while no difference in CHF or LVEF dysfunction was observed between the RYDAPT + chemotherapy and placebo + chemotherapy arms in the randomized AML study. In patients at risk, RYDAPT should be used with caution and patients should be closely monitored (at baseline and during treatment).
Pulmonary toxicity: Interstitial lung disease (ILD) and pneumonitis, some of which have been fatal, have occurred in patients treated with RYDAPT monotherapy or in combination with chemotherapy. Patients should be monitored for pulmonary symptoms indicative of ILD/pneumonitis and RYDAPT should be discontinued in patients who experience pulmonary symptoms indicative of ILD/pneumonitis which are ≥Grade 3 (NCI CTCAE).
Embryo-fetal toxicity and lactation: Based on findings from animal studies, RYDAPT can cause fetal harm when administered to pregnant women. Administration of midostaurin to pregnant rats and rabbits during the period of organogenesis resulted in embryo-fetal toxicity. Pregnant women should be advised of the potential risk to a fetus; Females of reproductive potential should be advised to use effective contraception during treatment with Rydapt and for at least 4 months after stopping treatment.
Because of the potential for serious adverse effects in nursing infants from Rydapt, nursing women should be advised to discontinue breastfeeding during treatment with Rydapt and for at least 4 months after stopping treatment (see Use in Pregnancy & Lactation).
Females and males of reproductive potential: Pregnancy testing: Sexually-active females of reproductive potential are advised to have a pregnancy test prior to starting treatment with RYDAPT.
Contraception: Females of reproductive potential should be advised that animal studies show RYDAPT to be harmful to the developing fetus. Sexually-active females of reproductive potential should use effective contraception (methods that result in less than 1% pregnancy rates) when using RYDAPT and for at least 4 months after stopping treatment with RYDAPT. Sexually-active males taking RYDAPT should use a condom during intercourse with females of reproductive potential or pregnant women and for at least 4 months after stopping treatment with RYDAPT to avoid conception or embryo-fetal harm.
Infertility: RYDAPT may impair fertility in humans. Oral administration of midostaurin at 10, 30 and 60 mg/kg/day was associated with reproductive toxicity in male and female rats at 60 mg/kg/day. In males, testicular degeneration and atrophy, alterations in sperm motility, a decrease in sperm counts, and a decrease in reproductive organ weights were observed. In females, increased resorptions, decreased pregnancy rate, number of implants and live embryos were observed at 60 mg/kg/day. Inhibition of spermatogenesis was seen in dogs at doses ≥3 mg/kg/day. The concentrations in rats at 60 mg/kg/day and dogs at 3 mg/kg/day are 8- and 100-fold below the human therapeutic exposures at the recommended doses of 50 or 100 mg twice daily based on AUC.
Use In Pregnancy & Lactation
Pregnancy: Risk summary: RYDAPT can cause fetal harm when administered to a pregnant woman.
There are no adequate and well-controlled studies in pregnant women. Reproductive studies in rats and rabbits demonstrated that midostaurin induced fetotoxicity. An increase in number of late resorptions, a reduction in fetal weight and reduced skeletal ossification were observed in rats and rabbits following prenatal exposure to midostaurin at concentrations over 50–fold below the exposure in humans at the recommended doses of 50 and 100 mg twice daily based on AUC. Pregnant women should be advised of the potential risk to the fetus.
Animal data: In embryo-fetal development studies in rats and rabbits, pregnant animals received oral doses of midostaurin at 3, 10, and 30 mg/kg/day and at 2, 10 and 20 mg/kg/day, respectively, during the period of organogenesis. An increase in number of late resorptions was observed at all dose levels and a reduction in fetal weight and skeletal ossification was observed in rats at the high dose of 30 mg/kg/day; no maternal toxicity was observed. In rabbits, maternal toxicity was observed at all dose levels. Mortality in dams, reduced fetal weight and delayed ossification was observed at 10 and 20 mg/kg/day. The concentrations at which maternal and fetal toxicity occurred in both species are over 50-fold below the human therapeutic exposures at the recommended doses of 50 and 100 mg twice daily based on AUC comparisons across species. In a pre- and post-natal developmental study, rats were given oral doses of 5, 15, and 30 mg/kg/day during gestation through lactation up to weaning. Maternal toxicity including signs of dystocia and reduced litter size were observed at 30 mg/kg/day. Lower body weights, a delay in eye opening and auricular startle ontogeny were noted in the rat pups (F1 generation) exposed to midostaurin at 30 mg/kg/day. Maternal systemic exposure at 30 mg/kg (based on AUC) was over 200-fold below the human therapeutic exposures at the human doses of 50 and 100 mg twice daily.
Lactation: It is unknown whether midostaurin or its active metabolites are excreted in human milk. There are no data on the effects of RYDAPT on the breastfed child or the effects of RYDAPT on milk production. Studies show that orally administered midostaurin and its active metabolites pass into the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from RYDAPT, a nursing woman should be advised on the potential risks to the child and breast-feeding should be discontinued during treatment with RYDAPT and for at least 4 months after stopping treatment.
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.
Drug Interactions
Midostaurin undergoes extensive hepatic metabolism through CYP3A4 enzymes which are either induced or inhibited by a number of concomitant drugs. Based on in vitro data, midostaurin and/or its metabolites have the potential to inhibit and to induce CYP enzymes. Therefore, RYDAPT may be a victim or a perpetrator of drug-drug interactions in vivo.
Effect of other drugs on RYDAPT: Drugs or substances known to affect the activity of CYP3A4 may affect the plasma concentrations of midostaurin and therefore the safety and/or efficacy of RYDAPT.
Strong CYP3A4 inhibitors: Strong CYP3A4 inhibitors may increase midostaurin blood concentrations. In a study with 36 healthy subjects, co-administration of the strong CYP3A4 inhibitor ketoconazole to steady-state with a single dose of RYDAPT led to a significant increase in midostaurin exposure (1.8-fold Cmax increase and 10-fold AUCinf increase) while the peak concentrations of the active metabolites, CGP62221 and CGP52421, decreased by half (see Pharmacology under Actions). Another study evaluated the concomitant administration of multiple dose midostaurin 50 mg twice daily with the strong CYP3A4 inhibitor itraconazole at steady-state in a subset of patients (N=7), and showed that itraconazole increased midostaurin steady-state exposure (Cmin) by only 2.09-fold. During the induction phase of the AML study, up to 62% of patients received midostaurin concomitantly with strong inhibitors of CYP3A4. Upon co-administration with CYP3A4 inhibitors, a 1.44-fold increase in midostaurin exposure (Cmin) was observed. No impact was observed for CGP62221 and CGP52421. Considering the time-dependent pharmacokinetics of midostaurin (see Pharmacology under Actions), the clinical relevance of the interaction of strong CYP3A4 inhibitors on midostaurin exposure seems limited. Caution should be advised when concomitantly administering with midostaurin, medicinal products that are strong inhibitors of CYP3A4, such as, but not limited to antifungals (e.g., ketoconazole), certain antivirals (e.g., ritonavir), macrolide antibiotics (e.g., clarithromycin), and nefazodone. Alternative therapeutics that do not strongly inhibit CYP3A4 activity should be considered. In situations where satisfactory therapeutic alternatives do not exist, patients should be closely monitored for toxicity.
Strong CYP3A4 inducers: Strong CYP3A4 inducers may decrease midostaurin blood concentrations. In a study in healthy subjects, co-administration of the strong CYP3A4 inducer rifampicin (600 mg daily) to steady state with a single dose of midostaurin decreased midostaurin Cmax by 73% and AUCinf by 96%, respectively. Both metabolites, CGP62221 and CGP52421, exhibited a similar pattern. Avoid the concomitant use of RYDAPT with strong CYP3A4 inducers (e.g., carbamazepine, rifampin, St. John's Wort).
Effect of RYDAPT on other drugs: The PK of midazolam (sensitive CYP34A probe) was not affected following four dosing days of midostaurin in healthy subjects. While the dosing period only covered peak exposure to midostaurin, the data suggests that midostaurin is not a strong inducer of CYP3A4 (see Pharmacology under Actions).
Based on in vitro inhibition results, medicinal products with a narrow therapeutic range that are substrates of CYP3A4, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or OATP1B1 should be used with caution when administered concomitantly with midostaurin, and may need dose adjustment to maintain optimal exposure (see Pharmacology under Actions).
Drug-food interactions: See Pharmacology under Actions.
Caution For Usage
Incompatibilities: Not applicable.
ATC Classification
L01EX10 - midostaurin ; Belongs to the class of other protein kinase inhibitors. Used in the treatment of cancer.
Presentation/Packing
Soft cap 25 mg (pale orange oblong with red ink imprint "PKC NVR") x 56's.
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