RYDAPT 25mg capsule me medication leaflet

Rydapt 25 mg soft capsules

Each soft capsule contains 25 mg midostaurin.

Each soft capsule contains approximately 83 mg ethanol anhydrous and 415 mg macrogolglycerolhydroxystearate.

For the full list of excipients, see section 6.1.

Soft capsule (capsule).

Pale orange, oblong capsule with red imprint “PKC NVR”. The dimensions of the capsule areapproximately 25.4 x 9.2 mm.

Rydapt is indicated:

* in combination with standard daunorubicin and cytarabine induction and high-dose cytarabineconsolidation chemotherapy, and for patients in complete response followed by Rydapt singleagent maintenance therapy, for adult patients with newly diagnosed acute myeloid leukaemia(AML) who are FLT3 mutation-positive (see section 4.2);

* as monotherapy for the treatment of adult patients with aggressive systemic mastocytosis(ASM), systemic mastocytosis with associated haematological neoplasm (SM-AHN), or mastcell leukaemia (MCL).

Treatment with Rydapt should be initiated by a physician experienced in the use of anti-cancertherapies.

Before taking midostaurin, AML patients must have confirmation of FLT3 mutation (internal tandemduplication [ITD] or tyrosine kinase domain [TKD]) using a validated test.

Rydapt should be taken orally twice daily at approximately 12-hour intervals. The capsules should betaken with food (see sections 4.5 and 5.2).

Prophylactic antiemetics should be administered in accordance with local medical practice as perpatient tolerance.

AML

The recommended dose of Rydapt is 50 mg orally twice daily.

Rydapt is dosed on days 8-21 of induction and consolidation chemotherapy cycles, and then forpatients in complete response every day as single agent maintenance therapy until relapse for up to12 cycles of 28 days each (see section 4.1). In patients receiving a haematopoietic stem cell transplant(SCT), Rydapt should be discontinued 48 hours prior to the conditioning regimen for SCT.

Dose modifications in AML

Recommendations for dose modifications of Rydapt in patients with AML are provided in Table 1.

Table 1 Rydapt dose interruption, reduction and discontinuation recommendations inpatients with AML

Phase Criteria Rydapt dosing

Induction, Grade 3/4 pulmonary Interrupt Rydapt for the remainder of the cycle.

consolidation and infiltrates Resume Rydapt at the same dose when infiltratemaintenance resolves to Grade ≤1.

Other Grade 3/4 Interrupt Rydapt until toxicities considered atnon-haematological toxicities least possibly related to Rydapt have resolved to

Grade ≤2, then resume Rydapt.

QTc interval >470 msecs and Decrease Rydapt to 50 mg once daily for the≤500 msecs remainder of the cycle. Resume Rydapt at theinitial dose in the next cycle provided that QTcinterval improves to ≤470 msecs at the start ofthat cycle. Otherwise continue Rydapt 50 mgonce daily.

QTc interval >500 msecs Withhold or interrupt Rydapt for the remainderof the cycle. If QTc improves to ≤470 msecs justprior to the next cycle, resume Rydapt at theinitial dose. If QTc interval is not improved intime to start the next cycle do not administer

Rydapt during that cycle. Rydapt may be heldfor as many cycles as necessary until QTcimproves.

Maintenance only Grade 4 neutropenia (ANC Interrupt Rydapt until ANC ≥1.0 x 109/l, then<0.5 x 109/l) resume at 50 mg twice daily.

If neutropenia (ANC <1.0 x 109/l)persists >2 weeks and is suspected to be relatedto Rydapt, discontinue Rydapt.

Persistent Grade 1/2 toxicity Persistent Grade 1 or 2 toxicity that patientsdeem unacceptable may prompt an interruptionfor as many as 28 days.

ANC: Absolute Neutrophil Count

ASM, SM-AHN and MCL

The recommended starting dose of Rydapt is 100 mg orally twice daily.

Treatment should be continued as long as clinical benefit is observed or until unacceptable toxicityoccurs.

Dose modifications in ASM, SM-AHN and MCL

Recommendations for dose modifications of Rydapt in patients with ASM, SM-AHN and MCL areprovided in Table 2.

Table 2 Rydapt dose interruption, reduction and discontinuation recommendations inpatients with ASM, SM-AHN or MCL

Criteria Rydapt dosing

ANC <1.0 x 109/l attributed to Rydapt in patients Interrupt Rydapt until ANC ≥1.0 x 109/l, thenwithout MCL, or ANC less than 0.5 x 109/l resume at 50 mg twice daily and, if tolerated,attributed to Rydapt in patients with baseline increase to 100 mg twice daily.

ANC value of 0.5-1.5 x 109/l Discontinue Rydapt if low ANC persistsfor >21 days and is suspected to be related to

Rydapt.

Platelet count less than 50 x 109/l attributed to Interrupt Rydapt until platelet count greater than

Rydapt in patients without MCL, or platelet count or equal to 50 x 109/l, then resume Rydapt atless than 25 x 109/l attributed to Rydapt in 50 mg twice daily and, if tolerated, increase topatients with baseline platelet count of 100 mg twice daily.

25-75 x 109/l Discontinue Rydapt if low platelet count persistsfor >21 days and is suspected to be related to

Rydapt.

Haemoglobin less than 8 g/dl attributed to Rydapt Interrupt Rydapt until haemoglobin greater thanin patients without MCL, or life-threatening or equal to 8 g/dl, then resume Rydapt at 50 mganaemia attributed to Rydapt in patients with twice daily and, if tolerated, increase to 100 mgbaseline haemoglobin value of 8-10 g/dl twice daily.

Discontinue Rydapt if low haemoglobin persistsfor >21 days and is suspected to be related to

Rydapt.

Grade 3/4 nausea and/or vomiting despite optimal Interrupt Rydapt for 3 days (6 doses), then resumeanti-emetic therapy at 50 mg twice daily and, if tolerated, graduallyincrease to 100 mg twice daily.

Other Grade 3/4 non-haematological toxicities Interrupt Rydapt until event has resolved to

Grade ≤2, then resume Rydapt at 50 mg twicedaily and, if tolerated, increase to 100 mg twicedaily.

Discontinue Rydapt if toxicity is not resolved to

Grade ≤2 within 21 days or severe toxicity recursat a reduced dose of Rydapt.

ANC: Absolute Neutrophil Count

CTCAE severity: Grade 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms;4 = life-threatening symptoms.

If a dose is missed, the patient should take the next dose at the scheduled time.

If vomiting occurs, the patient should not take an additional dose of Rydapt but should take the nextscheduled dose.

Elderly (≥65 years)

No dose adjustment is required in patients aged over 65 years (see section 5.2). In patients aged≥60 years, Rydapt should be used only in patients eligible to receive intensive induction chemotherapywith adequate performance status and without significant comorbidities.

No dose adjustment is required for patients with mild or moderate renal impairment. Clinicalexperience in patients with severe renal impairment is limited and no data are available in patientswith end-stage renal disease (see sections 4.4 and 5.2).

No dose adjustment is required in patients with mild or moderate (Child-Pugh A or B) hepaticimpairment (see section 5.2). Exposure to midostaurin and its active metabolite CGP62221 issubstantially lower in patients with severe hepatic impairment than that in patients with normal hepaticfunction (see section 5.2). However, there are insufficient efficacy data in patients with severe hepaticimpairment to suggest a dose adjustment is required.

Acute promyelocytic leukaemia

Rydapt has not been studied in patients with acute promyelocytic leukaemia and therefore its use is notrecommended in this patient population.

Rydapt should not be used in combination with intensive paediatric AML combination chemotherapyregimens including anthracyclines, fludarabine and cytarabine because of the risk of prolongedhaematological recovery (such as prolonged severe neutropenia and thrombocytopenia) (seesections 4.4 and 5.1).

Rydapt is for oral use.

The capsules should be swallowed whole with a glass of water. They should not be opened, crushed orchewed to ensure proper dosing and avoid the unpleasant taste of the capsule content.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Concomitant administration of potent CYP3A4 inducers, e.g. rifampicin, St. John’s Wort (Hypericumperforatum), carbamazepine, enzalutamide, phenytoin (see section 4.5).

Neutropenia and infections

Neutropenia has occurred in patients receiving Rydapt as monotherapy and in combination withchemotherapy (see section 4.8). Severe neutropenia (ANC <0.5 x 109/l) was generally reversible bywithholding Rydapt until recovery and discontinuation in the ASM, SM-AHN and MCL studies.

White blood cell counts (WBCs) should be monitored regularly, especially at treatment initiation.

In patients who develop unexplained severe neutropenia, treatment with Rydapt should be interrupteduntil ANC is ≥1.0 x 109/l, as recommended in Tables 1 and 2. Rydapt should be discontinued inpatients who develop recurrent or prolonged severe neutropenia that is suspected to be related to

Rydapt (see section 4.2).

Any active serious infection should be under control prior to starting treatment with Rydaptmonotherapy. Patients should be monitored for signs and symptoms of infection, including anydevice-related infections, and if a diagnosis of infection is made appropriate treatment must beinstituted promptly, including, as needed, the discontinuation of Rydapt.

Cardiac dysfunction

Patients with symptomatic congestive heart failure were excluded from clinical studies. In the ASM,

SM-AHN and MCL studies cardiac dysfunction such as congestive heart failure (CHF) (includingsome fatalities) and transient decreases in left ventricular ejection fraction (LVEF) occurred. In therandomised AML study no difference in CHF was observed between the Rydapt + chemotherapy andplacebo + chemotherapy arms. In patients at risk, Rydapt should be used with caution and the patientclosely monitored by assessing LVEF when clinically indicated (at baseline and during treatment).

An increased frequency of QTc prolongation was noted in midostaurin-treated patients (seesection 4.8), however, a mechanistic explanation for this observation was not found. Caution iswarranted in patients at risk of QTc prolongation (e.g. due to concomitant medicinal products and/orelectrolyte disturbances). Interval assessments of QT by ECG should be considered if Rydapt is takenconcurrently with medicinal products that can prolong QT interval.

Interstitial lung disease (ILD) and pneumonitis, in some cases fatal, have occurred in patients treatedwith Rydapt monotherapy or in combination with chemotherapy. Patients should be monitored forpulmonary symptoms indicative of ILD or pneumonitis and Rydapt discontinued in patients whoexperience pulmonary symptoms indicative of ILD or pneumonitis without an infectious aetiology thatare ≥Grade 3 (NCI CTCAE).

Embryofoetal toxicity and breast-feeding

Pregnant women should be informed of the potential risk to a foetus; females of reproductive potentialshould be advised to have a pregnancy test within 7 days prior to starting treatment with Rydapt and touse effective contraception during treatment with Rydapt and for at least 4 months after stoppingtreatment.

Because of the potential for serious adverse reactions in breast-feeding infants from Rydapt, womenshould discontinue breast-feeding during treatment with Rydapt and for at least 4 months afterstopping treatment (see section 4.6).

Rydapt should not be used in combination with intensive paediatric AML combinationchemotherapy regimens including anthracyclines, fludarabine and cytarabine because of the risk ofprolonged haematological recovery (such as prolonged severe neutropenia and thrombocytopenia)(see sections 4.2 and 5.1).

Caution is warranted when considering the administration of midostaurin in patients with severe renalimpairment or end-stage renal disease and patients should be carefully monitored for toxicity (seesection 5.2).

Caution is required when concomitantly prescribing with midostaurin medicinal products that arestrong inhibitors of CYP3A4, such as, but not limited to, antifungals (e.g. ketoconazole), certainantivirals (e.g. ritonavir), macrolide antibiotics (e.g. clarithromycin) and nefazodone because they canincrease the plasma concentrations of midostaurin especially when (re-)starting with midostaurintreatment (see section 4.5). Alternative medicinal products that do not strongly inhibit CYP3A4activity should be considered. In situations where satisfactory therapeutic alternatives do not exist,patients should be closely monitored for midostaurin-related toxicity.

This medicinal product contains macrogolglycerol hydroxystearate, which may cause stomachdiscomfort and diarrhoea.

This medicinal product contains 666 mg of alcohol (ethanol) in each 200 mg dose (maximum dailydose), which is equivalent to 14 vol. % ethanol anhydrous. The amount in a 200 mg dose of thismedicine is equivalent to 17 ml beer or 7 ml wine. The small amount of alcohol in this medicine willnot have any noticeable effects. Alcohol may be harmful in patients with alcohol-related problems,epilepsy or liver problems or during pregnancy or breast-feeding.

Midostaurin undergoes extensive hepatic metabolism mainly through CYP3A4 enzymes which areeither induced or inhibited by a number of concomitant medicinal products.

Effect of other medicinal products on Rydapt

Medicinal products or substances known to affect the activity of CYP3A4 may affect the plasmaconcentrations of midostaurin and therefore the safety and/or efficacy of Rydapt.

Concomitant use of Rydapt with strong inducers of CYP3A4 (e.g. carbamazepine, rifampicin,enzalutamide, phenytoin, St. John’s Wort [Hypericum perforatum]) is contraindicated (seesection 4.3). Strong CYP3A4 inducers decrease exposure of midostaurin and its active metabolites(CGP52421 and CGP62221). In a study in healthy subjects, co-administration of the strong CYP3A4inducer rifampicin (600 mg daily) to steady state with a 50 mg single dose of midostaurin decreasedmidostaurin Cmax by 73% and AUCinf by 96% on average, respectively. CGP62221 exhibited a similarpattern. The mean AUClast of CGP52421 decreased by 60%.

Strong CYP3A4 inhibitors

Strong CYP3A4 inhibitors may increase midostaurin blood concentrations. In a study with 36 healthysubjects, co-administration of the strong CYP3A4 inhibitor ketoconazole to steady state with a singledose of 50 mg midostaurin led to a significant increase in midostaurin exposure (1.8-fold Cmax increaseand 10-fold AUCinf increase) and 3.5-fold increase in AUCinf of CGP62221, while the Cmax of theactive metabolites (CGP62221 and CGP52421) decreased by half (see section 5.2). At steady state ofmidostaurin (50 mg twice daily for 21 days), with the strong CYP3A4 inhibitor itraconazole at steadystate in a subset of patients (N=7), midostaurin steady-state exposure (Cmin) was increased by2.09-fold. Cmin of CGP52421 was increased by 1.3-fold, whereas no significant effect in exposure of

CGP62221 was observed (see section 4.4).

Effect of Rydapt on other medicinal products

Substrates of CYP enzymes

In healthy subjects, co-administration of a single dose of bupropion (CYP2B6 substrate) with multipledoses of midostaurin (50 mg twice daily) at steady state decreased bupropion AUCinf and AUClast by48% and 49% respectively and Cmax by 55% compared to administration of bupropion alone. Thisindicates that midostaurin is a mild inducer of CYP2B6. Medicinal products with a narrow therapeuticrange that are substrates of CYP2B6 (e.g. bupropion or efavirenz) should be used with caution whenadministered concomitantly with midostaurin, and may need dose adjustment to maintain optimalexposure.

Based on in-vitro data, midostaurin and its active metabolites, CGP52421 and CGP62221, areinhibitors of CYP1A2 and CYP2E1 and inducers of CYP1A2. Therefore, medicinal products with anarrow therapeutic range that are substrates of CYP1A2 (e.g. tizanidine) and CYP2E1 (e.g.

chlorzoxazone) should be used with caution when administered concomitantly with midostaurin, andmay need dose adjustment to maintain optimal exposure.

Substrates of transporters

In healthy subjects, co-administration of a single dose of rosuvastatin (BCRP substrate) with a singledose of midostaurin (100 mg) increased rosuvastatin AUCinf and AUClast by 37% and 48%respectively; Cmax was approximately doubled (2.01 times) compared to administration of rosuvastatinalone. This indicates that midostaurin has a mild inhibitory effect on BCRP substrates. Medicinalproducts with a narrow therapeutic range that are substrates of the transporter BCRP (e.g. rosuvastatinor atorvastatin) should be used with caution when administered concomitantly with midostaurin, andmay need dose adjustment to maintain optimal exposure.

There was no clinically significant pharmacokinetic drug-drug interaction between multiple doses ofmidostaurin (50 mg twice daily) at steady state and oral contraceptives containing ethinyl estradiol andlevonorgestrel in healthy women. Therefore, it is not anticipated that the contraceptive reliability ofthis combination will be compromised by co-administration of midostaurin.

In healthy subjects, midostaurin absorption (AUC) was increased by an average of 22% when Rydaptwas co-administered with a standard meal and by an average of 59% when co-administered with ahigh-fat meal. Peak midostaurin concentration (Cmax) was reduced by 20% with a standard meal andby 27% with a high-fat meal versus on an empty stomach (see section 5.2).

Rydapt is recommended to be administered with food.

Women of childbearing potential should be informed that animal studies show midostaurin to beharmful to the developing foetus. Sexually active women of childbearing potential are advised to havea pregnancy test within 7 days prior to starting treatment with Rydapt and that they should useeffective contraception (methods that result in less than 1% pregnancy rates) when using Rydapt andfor at least 4 months after stopping treatment with Rydapt.

Midostaurin can cause foetal harm when administered to a pregnant woman. There are no adequateand well-controlled studies in pregnant women. Reproductive studies in rats and rabbits demonstratedthat midostaurin induced foetotoxicity (see section 5.3). Rydapt is not recommended during pregnancyor in women of childbearing potential not using contraception. Pregnant women should be advised ofthe potential risk to the foetus.

It is unknown whether midostaurin or its active metabolites are excreted in human milk. Availableanimal data have shown that midostaurin and its active metabolites pass into the milk of lactating rats.

Breast-feeding should be discontinued during treatment with Rydapt and for at least 4 months afterstopping treatment.

There are no data on the effect of Rydapt on human fertility. Animal studies with midostaurin haveshown impaired fertility (see section 5.3).

Rydapt has minor influence on the ability to drive and use machines. Dizziness and vertigo have beenreported in patients taking Rydapt and should be considered when assessing a patient’s ability to driveor use machines.

AML

The safety evaluation of Rydapt (50 mg twice daily) in patients with newly diagnosed FLT3-mutated

AML is based on a phase III, randomised, double-blind, placebo-controlled study with 717 patients.

The overall median duration of exposure was 42 days (range 2 to 576 days) for patients in the Rydaptplus standard chemotherapy arm versus 34 days (range 1 to 465 days) for patients in the placebo plusstandard chemotherapy arm. For the 205 patients (120 in Rydapt arm and 85 in placebo arm) whoentered the maintenance phase, the median duration of exposure in maintenance was 11 months forboth arms (16 to 520 days for patients in the Rydapt arm and 22 to 381 days in the placebo arm).

The most frequent adverse reactions (ARs) in the Rydapt arm were febrile neutropenia (83.4%),nausea (83.4%), exfoliative dermatitis (61.6%), vomiting (60.7%), headache (45.9%), petechiae(35.8%) and pyrexia (34.5%). The most frequent Grade 3/4 ARs were febrile neutropenia (83.5%),lymphopenia (20.0%), device-related infection (15.7%), exfoliative dermatitis (13.6%),hyperglycaemia (7.0%) and nausea (5.8%). The most frequent laboratory abnormalities werehaemoglobin decreased (97.3%), ANC decreased (86.7%), ALT increased (84.2%), AST increased(73.9%) and hypokalaemia (61.7%). The most frequent Grade 3/4 laboratory abnormalities were ANCdecreased (85.8%), haemoglobin decreased (78.5%), ALT increased (19.4%) and hypokalaemia(13.9%).

Serious ARs occurred at similar rates in patients in the Rydapt versus the placebo arm. The mostfrequent serious AR in both arms was febrile neutropenia (16%).

Discontinuation due to any adverse reaction occurred in 3.1% of patients in the Rydapt arm versus1.3% in the placebo arm. The most frequent Grade 3/4 adverse reaction leading to discontinuation inthe Rydapt arm was exfoliative dermatitis (1.2%).

Safety profile during maintenance phase

While Table 3 provides the incidence for ARs over the total duration of the study, when themaintenance phase (single agent Rydapt or placebo) was assessed separately, a difference in the typeand severity of ARs was observed. The overall incidence of ARs during the maintenance phase wasgenerally lower than during the induction and consolidation phase. Incidences of ARs were, however,higher in the Rydapt arm than in the placebo arm during the maintenance phase. ARs occurring moreoften in the midostaurin arm versus placebo during maintenance included: nausea (46.4% versus17.9%), hyperglycaemia (20.2% versus 12.5%), vomiting (19% versus 5.4%) and QT prolongation(11.9% versus 5.4%).

Most of the haematological abnormalities reported occurred during the induction and consolidationphase when the patients received Rydapt or placebo in combination with chemotherapy. The mostfrequent Grade 3/4 haematological abnormalities reported in patients during the maintenance phasewith Rydapt were ANC decrease (20.8% versus 18.8%) and leukopenia (7.5% versus 5.9%).

ARs reported during the maintenance phase led to discontinuation of 1.2% of patients in the Rydaptarm and none in the placebo arm.

ASM, SM-AHN and MCL

The safety of Rydapt (100 mg twice daily) as a single agent in patients with ASM, SM-AHN and

MCL was evaluated in 142 patients in two single-arm, open-label, multicentre studies. The medianduration of exposure to Rydapt was 11.4 months (range: 0 to 81 months).

The most frequent ARs were nausea (82%), vomiting (68%), diarrhoea (51%), peripheral oedema(35%) and fatigue (31%). The most frequent Grade 3/4 ARs were fatigue (8.5%), sepsis (7.7%),pneumonia (7%), febrile neutropenia (7%), and diarrhoea (6.3%). The most frequentnon-haematological laboratory abnormalities were hyperglycaemia (93.7%), total bilirubin increased(40.1%), lipase increased (39.4%), aspartate aminotransferase (AST) increased (33.8%), and alanineaminotransferase (ALT) increased (33.1%), while the most frequent haematological laboratoryabnormalities were absolute lymphocyte count decreased (73.2%) and ANC decreased (58.5%). Themost frequent Grade 3/4 laboratory abnormalities were absolute lymphocyte count decreased (45.8%),

ANC decreased (26.8%), hyperglycaemia (19%), and lipase increased (17.6%).

Dose modifications (interruption or adjustment) due to ARs occurred in 31% of patients. The mostfrequent ARs that led to dose modification (incidence ≥5%) were nausea and vomiting.

ARs that led to treatment discontinuation occurred in 9.2% of patients. The most frequent (incidence≥1%) were febrile neutropenia, nausea, vomiting and pleural effusion.

Tabulated lists of adverse reactions

ARs are listed according to MedDRA system organ class. Within each system organ class, the ARs areranked by frequency, with the most frequent reactions first, using the following convention (CIOMS

III): 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 availabledata). Within each frequency grouping, adverse reactions are presented in the order of decreasingseriousness.

AML

Table 3 presents the frequency category of ARs reported in the phase III study in patients with newlydiagnosed FLT3-mutated AML and during post-marketing experience.

Table 3 Adverse reactions observed in AML

All grades Grades 3/4

Rydapt + Rydapt +

Adverse reaction chemo chemo Frequency categoryn=2291 n=3451% %

Device-related infection 24 15.7 Very common

Upper respiratory tract infection 5.2 0.6 Common

Neutropenic sepsis 0.9 3.5 Uncommon

Febrile neutropenia 83.4 83.5 Very common

Petechiae 35.8 1.2 Very common

Lymphopenia 16.6 20 Very common

Hypersensitivity 15.7 0.6 Very common

Hyperuricaemia 8.3 0.6 Common

Insomnia 12.2 0 Very common

Headache 45.9 2.6 Very common

Syncope 5.2 4.6 Common

Tremor 3.9 0 Common

Eyelid oedema 3.1 0 Common

Hypotension 14.4 5.5 Very common

Sinus tachycardia 9.6 1.2 Common

Hypertension 7.9 2.3 Common

Pericardial effusion 3.5 0.6 Common

Epistaxis 27.5 2.6 Very common

Laryngeal pain 11.8 0.6 Very common

Interstitial lung disease/Pneumonitis2 11.4 4.9 Very common

Dyspnoea 10.9 5.5 Very common

Pleural effusion 5.7 0.9 Common

Nasopharyngitis 8.7 0 Common

Acute respiratory distress syndrome 2.2 2.3 Common

Nausea 83.4 5.8 Very common

Vomiting 60.7 2.9 Very common

Stomatitis 21.8 3.5 Very common

Abdominal pain upper 16.6 0 Very common

Haemorrhoids 15.3 1.4 Very common

Anorectal discomfort 7 0.9 Common

Abdominal discomfort 3.5 0 Common

Dermatitis exfoliative 61.6 13.6 Very common

Hyperhidrosis 14.4 0 Very common

Dry skin 7 0 Common

Keratitis 6.6 0.3 Common

Acute febrile neutrophilic dermatosis3 - - Not known

Back pain 21.8 1.4 Very common

Arthralgia 14 0.3 Very common

Bone pain 9.6 1.4 Common

Pain in extremity 9.6 1.4 Common

Neck pain 7.9 0.6 Common

Pyrexia 34.5 3.2 Very common

Catheter-related thrombosis 3.5 2 Common

Haemoglobin decreased* 97.3 78.5 Very common

ANC decreased* 86.7 85.8 Very common

ALT increased* 84.2 19.4 Very common

AST increased* 73.9 6.4 Very common

Hypokalaemia* 61.7 13.9 Very common

Hyperglycaemia 20.1 7 Very common

Hypernatraemia* 20 1.2 Very common

Electrocardiogram QT prolonged3 19.7 5.8 Very common

Activated partial thromboplastin time 12.7 2.6 Very commonprolonged

Hypercalcaemia* 6.7 0.6 Common

Weight increased 6.6 0.6 Common1For trial sites in North America, all grades were collected for 13 pre-specified adverse events. For allother adverse events, only grades 3 and 4 were collected. Therefore, all grade AEs are summarisedonly for patients in non-North American trial sites, whereas Grades 3 and 4 are summarised forpatients in all trial sites.2This AR was included after identification in the post-marketing setting. Interstitial lung disease hasbeen derived from post-marketing experience with Rydapt via spontaneous case reports and literaturecases. No cases of interstitial lung disease were reported in the phase III study.3These ARs were included after identification in the post-marketing setting.

* Frequency is based on laboratory values.

ASM, SM-AHN and MCL

Table 4 presents the frequency category of ARs based on pooled data from two studies in patients with

ASM, SM-AHN and MCL.

Table 4 Adverse reactions observed in ASM, SM-AHN and MCL

Adverse reaction Rydapt (100 mg twice daily) Frequency category

N=142

All grades Grades 3/4% %

Urinary tract infection 13 2.8 Very common

Upper respiratory tract infection 11 1.4 Very common

Pneumonia 8.5 7.0 Common

Sepsis 7.7 7.7 Common

Bronchitis 5.6 0 Common

Oral herpes 4.9 0 Common

Cystitis 4.2 0 Common

Sinusitis 4.2 0.7 Common

Erysipelas 3.5 1.4 Common

Herpes zoster 3.5 0.7 Common

Febrile neutropenia 7.7 7.0 Common

Hypersensitivity 2.1 0 Common

Anaphylactic shock 0.7 0.7 Uncommon

Headache 26 1.4 Very common

Dizziness 13 0 Very common

Disturbance in attention 7 0 Common

Tremor 6.3 0 Common

Ear and labyrinth disorders

Vertigo 4.9 0 Common

Hypotension 9.2 2.1 Common

Haematoma 6.3 0.7 Common

Dyspnoea 18 5.6 Very common

Cough 16 0.7 Very common

Pleural effusion 13 4.2 Very common

Epistaxis 12 2.8 Very common

Oropharyngeal pain 4.2 0 Common

Interstitial lung disease/Pneumonitis1 2.1 0 Common

Nausea 82 5.6 Very common

Vomiting 68 5.6 Very common

Diarrhoea 51 6.3 Very common

Constipation 29 0.7 Very common

Dyspepsia 5.6 0 Common

Gastrointestinal haemorrhage 4.2 3.5 Common

Oedema peripheral 35 3.5 Very common

Fatigue 31 8.5 Very common

Pyrexia 27 4.2 Very common

Asthenia 4.9 0.7 Common

Chills 4.9 0 Common

Oedema 4.2 0.7 Common

Hyperglycaemia (non-fasting)* 93.7 19.0 Very common

Absolute lymphocyte decreased* 73.2 45.8 Very common

ANC decreased* 58.5 26.8 Very common

Total bilirubin increased* 40.1 4.9 Very common

Lipase increased* 39.4 17.6 Very common

AST increased* 33.8 2.8 Very common

ALT increased* 33.1 3.5 Very common

Amylase increased* 20.4 7.0 Very common

Electrocardiogram QT prolonged1 10.6 0.7 Very common

Weight increased 5.6 2.8 Common

Contusion 6.3 0 Common

Fall 4.2 0.7 Common

* Frequency is based on laboratory values.1These ARs were included after identification in the post-marketing setting.

Nausea, vomiting and diarrhoea were observed in AML, ASM, SM-AHN and MCL patients. In ASM,

SM-AHN and MCL patients these events led to dose adjustment or interruption in 26% and todiscontinuation in 4.2% of the patients. Most of the events occurred within the first 6 months oftreatment and were managed with supportive prophylactic medicinal products.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Reported experience with overdose in humans is very limited. Single doses of up to 600 mg have beengiven with acceptable acute tolerability. Adverse reactions observed were diarrhoea, abdominal painand vomiting.

There is no known specific antidote for midostaurin. In the event of an overdose, patients must beclosely monitored for signs or symptoms of adverse reactions, and appropriate symptomatic andsupportive treatment initiated.

Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors, ATC code: L01EX10

Midostaurin inhibits multiple receptor tyrosine kinases, including FLT3 and KIT kinase. Midostaurininhibits FLT3 receptor signalling and induces cell cycle arrest and apoptosis in leukaemic cellsexpressing FLT3 ITD or TKD mutant receptors or over-expressing FLT3 wild type receptors. In vitrodata indicate that midostaurin inhibits D816V mutant KIT receptors at exposure levels achieved inpatients (average achieved exposure higher than IC50). In vitro data indicate that KIT wild typereceptors are inhibited to a much lesser extent at these concentrations (average achieved exposurelower than IC50). Midostaurin interferes with aberrant KIT D816V-mediated signalling and inhibitsmast cell proliferation, survival and histamine release.

In addition, midostaurin inhibits several other receptor tyrosine kinases such as PDGFR(platelet-derived growth factor receptor) or VEGFR2 (vascular endothelial growth factor receptor 2),as well as members of the serine/threonine kinase family PKC (protein kinase C). Midostaurin binds tothe catalytic domain of these kinases and inhibits the mitogenic signalling of the respective growthfactors in cells, resulting in growth arrest.

Midostaurin in combination with chemotherapeutic agents (cytarabine, doxorubicin, idarubicin anddaunorubicin) resulted in synergistic growth inhibition in FLT3-ITD expressing AML cell lines.

Two major metabolites have been identified in murine models and humans, i.e. CGP62221 and

CGP52421. In proliferation assays with FLT3-ITD expressing cells, CGP62221 showed similarpotency compared to the parent compound, however CGP52421 was approximately 10-fold lesspotent.

A dedicated QT study in 192 healthy subjects with a dose of 75 mg twice daily did not revealclinically significant prolongation of QT by midostaurin and CGP62221 but the study duration was notlong 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 bothmetabolites was further explored in a phase II study in 116 patients with ASM, SM-AHN or MCL. Atthe 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, sincethe upper bounds of predicted change at these concentration levels were less than 10 msecs (5.8, 2.4,and 4.0 msecs, respectively). In the ASM, SM-AHN and MCL population, 25.4% of patients had atleast one ECG measurement with a QTcF greater than 450 ms and 4.7% greater than 480 ms.

AML

The efficacy and safety of midostaurin in combination with standard chemotherapy versus placeboplus standard chemotherapy and as single agent maintenance therapy was investigated in 717 patients(18 to 60 years of age) in a randomised, double-blind, phase III study. Patients with newly diagnosed

FLT3-mutated AML as determined by a clinical study assay were randomised (1:1) to receivemidostaurin 50 mg twice daily (n=360) or placebo (n=357) sequentially in combination with standarddaunorubicin (60 mg/m2 daily on days 1-3)/cytarabine (200 mg/m2 daily on days 1-7) induction andhigh-dose cytarabine (3 g/m2 every 12 hours on days 1, 3, 5) consolidation, followed by continuousmidostaurin 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 cytogeneticabnormalities, patients with acute promyelocytic leukaemia (M3) or therapy-related AML wereexcluded. Patients were stratified by FLT3 mutation status: TKD, ITD with allelic ratio <0.7, and ITDwith allelic ratio ≥0.7.

The two treatment groups were generally balanced with respect to the baseline demographics ofdisease characteristics. The median age of the patients was 47 years (range: 18 to 60 years), a majorityof the patients had ECOG performance status of 0 or 1 (88.3%), and most patients had de novo AML(95%). Of the patients with race information reported, 88.1% were Caucasian. The majority of patients(77.4%) had FLT3-ITD mutations, most of them (47.6%) with a low allelic ratio (<0.7), and 22.6% ofpatients had FLT3-TKD mutations. Forty-eight per cent were male in the midostaurin arm and 41% inthe placebo arm.

Patients who proceeded to haematopoietic stem cell transplant (SCT) stopped receiving studytreatment prior to the start of the SCT conditioning regimen. The overall rate of SCT was 59.4%(214/360) of patients in the midostaurin plus standard chemotherapy arm versus 55.2% (197/357) inthe 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 randomisationuntil death by any cause. The primary analysis was conducted after a minimum follow-up ofapproximately 3.5 years after the randomisation of the last patient. The study demonstrated astatistically significant improvement in OS with a 23% risk reduction of death for midostaurin plusstandard chemotherapy over placebo plus standard chemotherapy (see Table 6 and Figure 1).

Figure 1 Kaplan-Meier curve for overall survival, non-censored for SCT

Midostaurin (n=360)

Median: 74.7 months

Placebo (n=357)80 Median: 25.6 months

HR: 0.774 (95% CI, 0.629-0.953)

P = 0.00780 6 12 18 24 30 36 42 48 54 60 66 72 78 84

Months

Patients at risk

Months 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84

Midostaurin 360 314 269 234 208 189 181 174 133 120 77 50 22 1 0

Placebo 357 284 221 179 163 152 148 141 110 95 71 45 20 1 0

The key secondary endpoint was event-free survival (EFS; an EFS event is defined as a failure toobtain a complete remission (CR) within 60 days of initiation of protocol therapy, or relapse, or deathfrom any cause). The EFS showed a statistically significant improvement for midostaurin plusstandard chemotherapy over placebo plus standard chemotherapy (HR: 0.78 [95% CI, 0.66 to 0.93]p = 0.0024), and a median EFS of 8.2 months and 3.0 months, respectively; see Table 5.

Overall survival probability, %

Table 5 Efficacy of midostaurin in AML

Efficacy parameter Midostaurin Placebo HR* P-value¥n=360 n=357 (95% CI)

Overall survival (OS)1

Median OS in months (95% CI) 74.7 (31.5, NE) 25.6 (18.6, 42.9) 0.77 (0.63, 0.95) 0.0078

Kaplan-Meier estimates at 5 years 0.51 (0.45, 0.56) 0.43 (0.38, 0.49)(95% CI)

Event-free survival (EFS)2

Median EFS in months, 8.2 (5.4, 10.7) 3.0 (1.9, 5.9) 0.78 (0.66, 0.93) 0.0024considering CRs within 60 days oftreatment start (95% CI)

Median EFS in months, 10.2 (8.1, 13.9) 5.6 (2.9, 6.7) 0.73 (0.61, 0.87) 0.0001considering CRs any time duringinduction (95% CI)

Disease-free survival (DFS)

Median DFS in months (95% CI) 26.7 (19.4, NE) 15.5 (11.3, 23.5) 0.71 (0.55, 0.92) 0.0051

Complete remission (CR)within 60 days of treatment start 212 (58.9) 191 (53.5) NE 0.073§(%)any time during induction (%) 234 (65.0) 207 (58.0) NE 0.027§

Cumulative incidence of relapse(CIR)

Median (95% CI) NE (25.7, NE) 17.6 (12.7, 46.3) 0.68 (0.52, 0.89) 0.00231primary endpoint; 2key secondary endpoint; NE: Not Estimated

*Hazard ratio (HR) estimated using Cox regression model stratified according to the randomisation FLT3mutation factor.¥1-sided p-value calculated using log-rank test stratified according to the randomisation FLT3 mutationfactor.§Not significant

There was a trend favouring midostaurin for CR rate by day 60 for the midostaurin arm (58.9% versus53.5%; 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 during induction, the cumulativeincidence of relapse at 12 months was 26% in the midostaurin arm versus 41% in the placebo arm.

Sensitivity analyses for both OS and EFS when censored at the time of SCT also supported the clinicalbenefit with midostaurin plus standard chemotherapy over placebo.

Results for OS by SCT status are shown in Figure 2. For EFS, considering complete remissions within60 days of study treatment start, the HR was 0.602 (95% CI: 0.372, 0.974) for patients with SCT and0.827 (95% CI: 0.689, 0.993) for patients without SCT, favouring midostaurin.

Figure 2 Kaplan Meier curve for overall survival by SCT status in AML100% Median

Survival

Subjects Event (months) 95% CI

MIDOSTAURIN - SCT 214 100 74.7 37.3 N.E.

PLACEBO - SCT80% 197 105 35.9 22.6 N.E.

MIDOSTAURIN - no SCT 146 71 31.7 16.9 N.E.

PLACEBO - no SCT 160 81 14.7 10.0 36.960%40%20% 1: MIDIDOOSTSATUARUINR -I SNC -T SCT2: PLACCEEBOB O- S -C STCT HR (95% CI) - SCT 0.780 (0.593, 1.026)3: MIDIDOOSTSATUARUINR -I nNo -S CnoT SCT HR (95% CI) - no SCT 0.798 (0.580, 1.098)4: PLACCEEBOB O- n -o nSoC TSCT0% Censored0 6 12 18 24 30 36 42 48 54 60 66 72 78 84

OOvveerraallll ssuurrvviviavla (lm (omnothnst)hs)

NoN. o. fo pf paatiteientts sttiillll a at tr isriksk1 214 207 178 154 137 122 117 112 84 76 50 33 12 1 02 197 184 151 118 105 97 93 90 67 58 42 28 12 1 03 146 107 91 80 71 67 64 62 49 44 27 17 10 04 160 100 70 61 58 55 55 51 43 37 29 17 8 0

In a subgroup analysis, no apparent OS benefit was observed in females, however, a treatment benefitwas observed in females in all secondary efficacy endpoints (see Table 6).

Table 6 Overview of OS, EFS, CR, DFS and CIR by gender in AML

Endpoint Overall Males Females95% CI 95% CI 95% CI

OS (HR) 0.774 0.533 1.007(0.629, 0.953) (0.392, 0.725) (0.757, 1.338)

EFS (CR induction) 0.728 0.660 0.825(HR) (0.613, 0.866) (0.506, 0.861) (0.656, 1.037)

CR induction (OR) 0.743* 0.675* 0.824*(0.550, 1.005) (0.425, 1.072) (0.552, 1.230)

DFS (CR induction) 0.663 0.594 0.778(HR) (0.516, 0.853) (0.408, 0.865) (0.554, 1.093)

CIR (CR induction) 0.676 0.662 0.742(HR) (0.515, 0.888) (0.436, 1.006) (0.516, 1.069)

*Odds ratio calculated as (No complete remission in treatment/Complete remission in treatment) /(No complete remission in placebo/complete remission in placebo)

HR= Hazard ratio; OR=odds ratio

Efficacy and safety in patients >60-70 years old were evaluated as part of a phase II, single-arm,investigator-initiated study of midostaurin in combination with intensive induction, consolidationincluding allogenic SCT and single-agent maintenance in patients with FLT3-ITD mutated AML.

Based on the final analysis, the EFS rate at 2 years (primary endpoint) was 34% (95% CI: 27, 44) andthe median OS was 22.7 months in patients older than 60 years of age (128 out of 440 patients).

ASM, SM-AHN and MCL

The efficacy of midostaurin in patients with ASM, SM-AHN and MCL, collectively referred to asadvanced systemic mastocytosis (SM), was evaluated in two open-label, single-arm, multicentrestudies (142 patients in total).

The pivotal study was a multicentre, single-arm phase II study in 116 patients with advanced SM(Study CPKC412D2201). Midostaurin was administered orally at 100 mg twice daily until diseaseprogression or intolerable toxicity. Of the 116 patients enrolled, 89 were considered eligible for

PPrroobbaabbiilliittyy ooff SSuurrvviivvaall ((%%))

Probability of Survival (%)response assessment and constituted the primary efficacy population. Of these, 73 patients had ASM(57 with an AHN) and 16 patients had MCL (6 with an AHN). The median age in the primary efficacypopulation was 64 years with approximately half of the patients ≥65 years. Approximately one third(36%) received prior anti-neoplastic therapy for ASM, SM-AHN or MCL. At baseline in the primaryefficacy population, 65% of the patients had >1 measurable C finding (thrombocytopenia,hypoalbuminaemia, anaemia, high total bilirubin, transfusion-dependent anaemia, weight loss,neutropenia, high ALT or high AST). The KIT D816V mutation was detected in 82% of patients.

The primary endpoint was overall response rate (ORR). Response rates were assessed based on themodified 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. Responsesto midostaurin are shown in Table 7. Activity was observed regardless of number of prior therapies,and presence or absence of an AHN. Confirmed responses were observed in both KIT D816Vmutation positive patients (ORR=63%) and KIT D816V wild type or unknown patients(ORR=43.8%). However, the median survival for KIT D816V positive patients was longer, i.e.

33.9 months (95% CI: 20.7, 42), than for KIT D816V wild type or unknown patients, i.e. 10 months(95% CI: 6.9, 17.4). Forty-six percent of patients had a decrease in bone marrow infiltration thatexceeded 50% and 58% had a decrease in serum tryptase levels that exceeded 50%. Spleen volumedecreased by ≥10% in 68.9% of patients with at least 1 post-baseline assessment (26.7% of patientshad 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 offollow-up was 43 months.

Table 7 Efficacy of midostaurin in ASM, SM-AHN and MCL: primary efficacy population

All ASM SM-AHN MCL

N=89 N=16 N=57 N=16

Primary endpoint

Overall response, n (%) 53 (59.6) 12 (75.0) 33 (57.9) 8 (50.0)(95% CI) (48.6, 69.8) (47.6, 92.7) (44.1, 70.9) (24.7, 75.3)

Major response, n 40 (44.9) 10 (62.5) 23 (40.4) 7 (43.8)(%)

Partial response, n 13 (14.6) 2 (12.5) 10 (17.5) 1 (6.3)(%)

Stable disease, n (%) 11 (12.4) 1 (6.3) 7 (12.3) 3 (18.8)

Progressive disease, n 10 (11.2) 1 (6.3) 6 (10.5) 3 (18.8)(%)

Secondary endpoints

Median duration of 18.6 (9.9, 34.7) 36.8 (5.5, NE) 10.7 (7.4, 22.8) NR (3.6, NE)response, months (95%

CI)

Median overall survival, 26.8 (17.6, 34.7) 51.1 (28.7, NE) 20.7 (16.3, 33.9) 9.4 (7.5, NE)months (95% CI)

Kaplan-Meier estimates 26.1 (14.6, 39.2) 34.8 (1.7, 76.2) 19.9 (8.6, 34.5) 33.7 (12.3, 56.8)at 5 years (95% CI)

NE: Not Estimated, NR: Not Reached

Patients who received non-study anti-neoplastic therapy were considered as having progressed at the timeof the new therapy.

Although the study was designed to be assessed with the modified Valent and Cheson criteria, as apost-hoc exploratory analysis, efficacy was also assessed per the 2013 International Working

Group - Myeloproliferative Neoplasms Research and Treatment - European Competence Network on

Mastocytosis (IWG-MRT-ECNM) consensus criteria. Response to Rydapt was determined using acomputational algorithm applied without any adjudication. Out of 116 patients, 113 had a C-finding asdefined by IWG response criteria (excluding ascites as a C-finding). All responses were consideredand required a 12-week confirmation (see Table 8).

Table 8 Efficacy of midostaurin in ASM, SM-AHN and MCL per IWG-MRT-ECNMconsensus criteria using an algorithmic approach

All patients ASM SM-AHN MCL Subtypeevaluated unknown

N=113 N=15 N=72 N=21 N=5

Overall response rate, n (%) 32 (28.3) 9 (60.0) 15 (20.8) 7 (33.3) 1 (20.0)(95% CI) (20.2, 37.6) (32.3, 83.7) (12.2, 32.0) (14.6, 57.0) (0.5, 71.6)

Best overall response, n (%)

Complete remission 1 (0.9) 0 0 1 ( 4.8) 0

Partial remission 17 (15.0) 5 (33.3) 8 (11.1) 3 (14.3) 1 (20.0)

Clinical improvement 14 (1 2.4) 4 (2 6.7) 7 (9 .7) 3 (1 4.3) 0

Duration of response*n/N (%) 11/32 (34.4) 4/9 (44.4) 4/15 (26.7) 3/7 (42.9) 0/1 (0.0)median (95% CI) NE 36.8 NE NE NE(27.0, NE) (10.3, 36.8) (17.3, NE) (4.1, NE)

Overall survivaln/N (%) 65/113 4/15 (26.7) 49/72 12/21 0/5 (0.0)(57.5) (68.1) (57.1)median (95% CI) 29.9 51.1 22.1 22.6 NE(20.3, 42.0) (34.7, NE) (16.8, 32.2) (8.3, NE)

*Confirmation period for responses: 12 weeks

Analysis excludes ascites as a C-finding.

Patients who received non-study anti-neoplastic therapy were considered as having progressed at thetime of the new therapy.

The supportive study was a single-arm, multicentre, open-label phase II study of 26 patients with

ASM, SM-AHN and MCL (CPKC412A2213). Midostaurin was administered orally at 100 mg twicedaily in cycles of 28 days. Lack of a major response (MR) or partial response (PR) by the end of thesecond cycle required discontinuation from the study treatment. Twenty (76.9%) patients had ASM(17 [85%] with AHN) and 6 patients (23.1%) had MCL (2 [33.3%] with AHN). The median age was64.5 years with half of the patients ≥65 years). At baseline, 88.5% had >1 C finding and 69.2% hadreceived at least one prior anti-neoplastic regimen.

The primary endpoint was ORR evaluated by the Valent criteria during the first two cycles oftreatment. Nineteen patients (73.1%; 95% CI = [52.2, 88.4]) achieved a response during the first twocycles of treatment (13 MR; 6 PR). The median duration of follow-up was 73 months, and the medianduration of response has not been reached. Median overall survival was 40.0 months (patients wereonly followed up for one year after treatment discontinuation for survival).

In a phase II study, midostaurin was investigated in combination with chemotherapy in newlydiagnosed paediatric patients with FLT3-mutated AML. Among the three FLT3-mutated AMLpatients enrolled in the study, two patients (10 and 14 years old) experienced dose limiting toxicities(DLTs) following the second induction cycle with midostaurin (at 30 mg/m2 twice daily) incombination with chemotherapy (containing cytarabine 2 g/m2/day, day 1-5; fludarabine30 mg/m2/day, day 1-5 and idarubicin 12 mg/m2/day, day 2, 4 and 6). Both patients showed markedlydelayed haematological recoveries (i.e. prolonged grade 4 thrombocytopenia lasting for 44 days in thefirst patient and 51 days in the second patient and grade 4 neutropenia lasting for 46 days in the secondpatient). In the first induction cycle both patients received midostaurin in combination with cytarabine,etoposide and idarubicin.

The European Medicines Agency has waived the obligation to submit the results of studies with

Rydapt in all subsets of the paediatric population in the treatment of malignant mastocytosis and mastcell leukaemia (see section 4.2 for information on paediatric use).

The European Medicines Agency has deferred the obligation to submit the results of studies with

Rydapt in one or more subsets of the paediatric population in the treatment of acute myeloidleukaemia (see section 4.2 for information on paediatric use).

Midostaurin is a compound with good absorption and poor solubility. Two of its metabolitesdemonstrated pharmacological activities (CGP52421 and CGP62221). Following multiple doses, thepharmacokinetics of midostaurin and CGP62221 were time-dependent, with an initial increaseobserved in the first week followed by a decline of concentrations until reaching steady state onday 28. CGP52421 concentrations do not appear to decline as significantly as for midostaurin and

CGP62221.

The absolute bioavailability of midostaurin following oral administration is not known.

In humans, the absorption of midostaurin was rapid after oral administration, with Tmax of totalradioactivity observed at 1-3 hours post dose. The population pharmacokinetic analysis indicated thatthe absorption in patients was less than dose proportional at doses >50 mg twice daily.

In healthy subjects, after administration of a single dose of 50 mg midostaurin with food, AUC ofmidostaurin was increased to 20 800 ng*h/ml and Cmax was decreased to 963 ng/ml (see section 4.5).

Similarly, for CGP52421 and CGP62221 AUC increased to 19 000 and 29 200 ng*h/ml and Cmaxdecreased to 172 and 455 ng/ml, respectively. Time to peak concentration was also delayed in thepresence of a high-fat meal. Tmax was delayed for all entities, midostaurin median Tmax was 3 h, and for

CGP52421 and CGP62221 Tmax was delayed to 6 and 7 hours respectively.

In clinical studies, the efficacy and safety of Rydapt were investigated following administration with alight meal. After oral administration of a single 100 mg dose of midostaurin under fed conditions in

ASM, SM-AHN and MCL patients, AUCinf, Cmax and Tmax were 49 600 ng*h/ml, 2 940 ng/ml and 3 h,respectively, for midostaurin. For CGP52421, AUC0-12h and Cmax were 2 770 ng*h/ml and 299 ng/ml,respectively. AUC0-12h and Cmax for CGP62221 were 8 700 ng*h/ml and 931 ng/ml, respectively. After100 mg bid multiple oral doses of midostaurin the Cmin,ss plasma midostaurin in AML and ASM, SM-

AHN, MCL patients were 919 and 1 060 ng/ml, respectively. The CGP62221 Cmin, ss in the AML andthe ASM, SM-AHN, MCL population were 1 610 ng/ml and 2 020 ng/ml, respectively. The

CGP52421, Cmin,ss in the AML and the ASM, SM-AHN, MCL population were 8 630 ng/ml and2 860 ng/ml, respectively.

Midostaurin has a tissue distribution of geometric mean of 95.2 l (Vz/F). Midostaurin and itsmetabolites are distributed mainly in plasma rather than red blood cells. In vitro data showedmidostaurin is more than 98% bound to plasma proteins, such as albumin, α1-acid glycoprotein (AGP)and lipoprotein.

Midostaurin is metabolised by CYP3A4 mainly via oxidative pathways. The major plasmacomponents included midostaurin and two major active metabolites, CGP62221 (via O-demethylation)and CGP52421 (via hydroxylation), accounting for 27.7±2.7% and 38.0±6.6%, respectively, of thetotal plasma exposure at 96 hours after a single 50 mg dose of midostaurin.

The median terminal half-lives of midostaurin, CGP62221 and CGP52421 in plasma areapproximately 20.9, 32.3 and 471 hours. The mean apparent plasma clearance (CL/F) was 2.4-3.1 l/hin healthy subjects. In AML and ASM, SM-AHN and MCL patients, population pharmacokineticestimates for clearance of midostaurin at steady state were 5.9 l/h and 4.4 l/h, respectively. The Human

Mass Balance study results indicated that faecal excretion is the major route of excretion (78% of thedose), and mostly as metabolites (73% of the dose), while unchanged midostaurin accounts for 3% ofthe dose. Only 4% of the dose is recovered in urine.

In general, midostaurin and its metabolites showed no major deviation from dose-proportionality aftera single dose in the range of 25 mg to 100 mg. However, there was a less than dose-proportionalincrease 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 initialincrease in plasma concentrations during the first week (peak Cmin) followed by a decline with time toa steady state after approximately 28 days (2.5-fold decrease). While the exact mechanism for thedeclining concentration of midostaurin is unclear, it is likely due to the auto-induction properties ofmidostaurin and its two active metabolite CGP52421 and CGP62221 on CYP3A4. Thepharmacokinetics of the CGP62221 metabolite showed a similar trend. However, CGP52421concentrations increased up to 2.5-fold for ASM, SM-AHN and MCL and up to 9-fold for AML,compared to midostaurin after one month of treatment.

In vitro evaluation of drug-drug interaction potential

Based on in vitro data, midostaurin and its active metabolites, CGP52421 and CGP62221, areconsidered inhibitors of CYP1A2 and CYP2E1 and inducers of CYP2B6 (induction mediated by

CAR) and CYP1A2 (induction mediated by AhR).

In vitro experiments demonstrated that midostaurin, CGP52421 and CPG62221 can potentially inhibit

BCRP and BSEP. Simulations using physiologically-based pharmacokinetic (PBPK) models predictedthat midostaurin given at a dose of 50 mg or 100 mg twice daily at steady state is unlikely to causeclinically relevant inhibition of OATP1B.

Based on population pharmacokinetic analyses no significant impact of age on the pharmacokineticsof midostaurin and its two active metabolites was identified for patients aged between 65 and 85 years.

In adult patients with ASM, SM-AHN and MCL or AML, no midostaurin dose adjustment is requiredbased on age.

Rydapt is not recommended to be used in children and adolescents (see section 4.2).

The pharmacokinetics of midostaurin in paediatric patients were explored in a phase I dose escalationmonotherapy study with 22 patients (12 aged 0-2 years and 10 aged 10-17 years) with AML or

MLL-rearranged ALL using a population pharmacokinetic approach. The pharmacokinetics ofmidostaurin were less than dose proportional with the doses of 30 mg/m2 and 60 mg/m2 after singleand multiple doses. Due to the limited pharmacokinetic data in paediatric patients, no comparison withmidostaurin pharmacokinetics in adults can be made.

Based on population pharmacokinetic model analyses of the effect of gender on clearance ofmidostaurin and its active metabolites, there was no statistically significant finding and the anticipatedchanges in exposure (<20%) were not deemed to be clinically relevant. No midostaurin doseadjustment is required based on gender.

There are no differences in the pharmacokinetic profile between Caucasian and Black subjects. Basedon a phase I study in healthy Japanese volunteers, pharmacokinetic profiles of midostaurin and itsmetabolites (CGP62221 and CGP52421) are similar compared to those observed in otherpharmacokinetic studies conducted in Caucasians and Blacks. No midostaurin dose adjustment isrequired based on ethnicity.

A dedicated hepatic impairment study assessed the systemic exposure of midostaurin after oraladministration of 50 mg twice daily for 6 days and a single 50 mg dose on day 7 in subjects withbaseline mild or moderate (Child-Pugh Class A or B, respectively) and following a single doseadministration of 50 mg in subjects with severe hepatic impairment (Child-Pugh Class C) incomparison to control subjects with normal hepatic function. The maximum concentration ofmidostaurin was reached between 2 and 3 hours after administration after single or repeated doses forall groups. On day 1, the AUC0-12 and Cmax were 8 130 ng*h/ml and 1 206 ng/ml, respectively, forhealthy subjects. AUC0-12 was decreased by 39% and 36% in subjects with mild and moderate hepaticimpairment, respectively. On day 7, AUCCtrough (exposure under the curve of Ctrough from day 1 today 7) was 5 410 ng*h/ml in healthy subjects and was decreased by 35% and 20% in subjects withmild and moderate hepatic impairment, respectively. AUCtau was decreased by 28% and 20% onday 7, respectively.

The subjects with severe hepatic impairment had a lower geometric mean Cmax and AUCinf ofmidostaurin compared to the control group (Cmax: 1 360 ng/ml, AUCinf: 30 100 ng.h/ml). Cmax and

AUCinf of midostaurin decreased on average by 78% and 59% respectively in subjects with severehepatic impairment.

Finally, the long-term data from patients were analysed using a population pharmacokinetic approach.

No impact of hepatic impairment could be identified in patients with mild or moderate hepaticimpairment in the ASM, SM-AHN, MCL and AML populations.

Overall, there was no increase in exposure (AUC) to plasma midostaurin and its metabolites(CGP62221 and CGP52421) in subjects with mild, moderate or severe hepatic impairment comparedto subjects with normal hepatic function. No dose adjustment is necessary for patients with baselinemild or moderate hepatic impairment. Exposure to midostaurin and its active metabolite CGP62221 issubstantially lower in patients with severe hepatic impairment than that in patients with normal hepaticfunction (see section 4.2). However, there are insufficient efficacy data in patients with severe hepaticimpairment to suggest a dose adjustment is required.

Renal elimination is a minor route of elimination for midostaurin. No dedicated renal impairmentstudy was conducted for midostaurin. Population pharmacokinetic analyses were conducted using datafrom clinical studies in patients with AML (n=180) and ASM, SM-AHN and MCL (n=141). Out of the321 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 showednormal renal function (CrCL >90 ml/min) at baseline. Based on the population pharmacokineticanalyses, midostaurin clearance was not significantly impacted by renal impairment and therefore nodose adjustment is necessary for patients with mild or moderate renal impairment.

Due to dose-limiting toxicity, clinical therapeutic exposure levels could not be reached in animals. Allanimal findings described below were observed at midostaurin exposure significantly lower thantherapeutic levels.

Safety pharmacology and single/repeated dose toxicity

Safety pharmacology studies indicate that midostaurin is unlikely to interfere with vital functions ofthe central nervous system. In vitro, midostaurin did not inhibit hERG channel activity up to the limitof solubility of 12 µM. The two major human metabolites GGP52421 and CGP62221 (also tested atthe limit of solubility) inhibited hERG current with moderate safety margins. In the repeat-dosestudies in dogs, a decrease in heart rate, prolongation of the P-Q interval, and sporadically occurringatrioventricular blocks were seen in individual animals.

In the repeat-dose studies, target organs for toxicity were the gastrointestinal tract (emesis in dogs andmonkeys, diarrhoea and mucosal alteration), testes (decreased spermatogenesis), bone marrow(hypocellularity) and lymphoid organs (depletion/atrophy). The effect on the bone marrow andlymphoid organs was accompanied by haematological changes of decreased white blood cells,lymphocytes and erythrocytic parameters. An increase in liver enzymes (ALT and AST) was seenconsistently in rats, and in dogs and monkeys in long-term studies of ≥3 months duration, withouthistopathological correlates.

In a fertility study in rats, midostaurin was associated with reduced fertility, testicular degenerationand atrophy, reduced sperm motility, oligo- and aspermia, increased resorptions, decreased pregnancyrate, number of implants and live embryos.

In embryo-foetal development studies in rats and rabbits, increased numbers of late resorptions,reduced foetal weight and reduced skeletal ossification were observed.

In a pre- and post-natal developmental study, maternal dystocia and reduced litter size, lower pupbody weights, accelerated complete eye opening and delayed auricular startle ontogeny were noted.

In a toxicity study in juvenile rats, midostaurin was administered from days 7 to 70 postpartum. Areduction in body weight, haemorrhage and mixed cell infiltration in the lungs, anderythrocytosis/erythrophagocytosis in the mesenteric lymph nodes were seen. There were no effects onphysical development, sensory function or behavioural function. Mating index, fertility index andconception rates were reduced at 0, 5 and 15 mg/kg/day, but not at 2 mg/kg/day.

In vitro and in vivo genotoxicity studies covering relevant genotoxicity endpoints showed no evidenceof mutagenic or clastogenic activity. No carcinogenicity studies have been performed.

ERA studies have shown that midostaurin has the potential to be persistent, bioaccumulative and toxicto the environment.

Macrogolglycerol hydroxystearate

Macrogol

Ethanol anhydrous

Maize oil mono-di-triglycerides

All-rac-alpha-tocopherol

Gelatin

Glycerol

Titanium dioxide (E171)

Iron oxide yellow (E172)

Iron oxide red (E172)

Purified water

Carmine (E120)

Hypromellose

Not applicable.

3 years.

This medicinal product does not require any special temperature storage conditions.

Store in the original container in order to protect from moisture.

PA/alu/PVC/alu blisters. One blister contains 4 soft capsules.

Packs containing 56 (2 packs of 28) or 112 (4 packs of 28) soft capsules.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/17/1218/001-002

Date of first authorisation: 18 September 2017

Date of latest renewal: 30 May 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu