4.1. Therapeutic indications

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 (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 mast cell leukaemia (MCL).

4.2. Posology and method of administration

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

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

Posology

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

Prophylactic antiemetics should be administered in accordance with local medical practice as per patient 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 for patients in complete response every day as single agent maintenance therapy until relapse for up to 12 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 in patients with AML

Phase

Criteria

Rydapt dosing

Induction, consolidation and maintenance

Grade 3/4 pulmonary infiltrates

Interrupt Rydapt for the remainder of the cycle. Resume Rydapt at the same dose when infiltrate resolves to Grade ≤ 1.

Other Grade 3/4 non-haematological toxicities

Interrupt Rydapt until toxicities considered at least possibly related to Rydapt have resolved to Grade ≤ 2, then resume Rydapt.

QTc interval >470 msecs and ≤ 500 msecs

Decrease Rydapt to 50 mg once daily for the remainder of the cycle. Resume Rydapt at the initial dose in the next cycle provided that QTc interval improves to ≤ 470 msecs at the start of that cycle. Otherwise continue Rydapt 50 mg once daily.

QTc interval >500 msecs

Withhold or interrupt Rydapt for the remainder of the cycle. If QTc improves to ≤ 470 msecs just prior to the next cycle, resume Rydapt at the initial dose. If QTc interval is not improved in time to start the next cycle do not administer Rydapt during that cycle. Rydapt may be held for as many cycles as necessary until QTc improves.

Maintenance only

Grade 4 neutropenia (ANC <0.5 x 109/l)

Interrupt Rydapt until ANC ≥1.0 x 109/l, then resume at 50 mg twice daily.

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

Persistent Grade 1/2 toxicity

Persistent Grade 1 or 2 toxicity that patients deem unacceptable may prompt an interruption for 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 toxicity occurs.

Dose modifications in ASM, SM-AHN and MCL

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

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

Criteria

Rydapt dosing

ANC <1.0 x 109/l attributed to Rydapt in patients without MCL, or ANC less than 0.5 x 109/l attributed to Rydapt in patients with baseline ANC value of 0.5-1.5 x 109/l

Interrupt Rydapt until ANC ≥1.0 x 109/l, then resume at 50 mg twice daily and, if tolerated, increase to 100 mg twice daily.

Discontinue Rydapt if low ANC persists for >21 days and is suspected to be related to Rydapt.

Platelet count less than 50 x 109/l attributed to Rydapt in patients without MCL, or platelet count less than 25 x 109/l attributed to Rydapt in patients with baseline platelet count of 25-75 x 109/l

Interrupt Rydapt until platelet count greater than or equal to 50 x 109/l, then resume Rydapt at 50 mg twice daily and, if tolerated, increase to 100 mg twice daily.

Discontinue Rydapt if low platelet count persists for >21 days and is suspected to be related to Rydapt.

Haemoglobin less than 8 g/dl attributed to Rydapt in patients without MCL, or life-threatening anaemia attributed to Rydapt in patients with baseline haemoglobin value of 8-10 g/dl

Interrupt Rydapt until haemoglobin greater than or equal to 8 g/dl, then resume Rydapt at 50 mg twice daily and, if tolerated, increase to 100 mg twice daily.

Discontinue Rydapt if low haemoglobin persists for >21 days and is suspected to be related to Rydapt.

Grade 3/4 nausea and/or vomiting despite optimal anti-emetic therapy

Interrupt Rydapt for 3 days (6 doses), then resume at 50 mg twice daily and, if tolerated, gradually increase 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 twice daily and, if tolerated, increase to 100 mg twice daily.

Discontinue Rydapt if toxicity is not resolved to Grade ≤ 2 within 21 days or severe toxicity recurs at 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.

Missed doses

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 next scheduled dose.

Special populations

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 chemotherapy with adequate performance status and without significant comorbidities.

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 and no data are available in patients with end-stage renal disease (see sections 4.4 and 5.2).

Hepatic impairment

No dose adjustment is required in patients with mild or moderate (Child-Pugh A or B) hepatic impairment (see section 5.2). Exposure to midostaurin and its active metabolite CGP62221 is substantially lower in patients with severe hepatic impairment than that in patients with normal hepatic function (see section 5.2). However, there are insufficient efficacy data in patients with severe hepatic impairment 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 not recommended in this patient population.

Paediatric population

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

Method of administration

Rydapt is for oral use.

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

4.3. Contraindications

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 (Hypericum perforatum), carbamazepine, enzalutamide, phenytoin (see section 4.5).

4.4. Special warnings and precautions for use

Neutropenia and infections

Neutropenia has occurred in patients receiving Rydapt as monotherapy and in combination with chemotherapy (see section 4.8). Severe neutropenia (ANC <0.5 x 109/l) was generally reversible by withholding 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 interrupted until ANC is ≥1.0 x 109/l, as recommended in Tables 1 and 2. Rydapt should be discontinued in patients 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 Rydapt monotherapy. Patients should be monitored for signs and symptoms of infection, including any device-related infections, and if a diagnosis of infection is made appropriate treatment must be instituted 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) (including some fatalities) and transient decreases in left ventricular ejection fraction (LVEF) occurred. In the randomised AML study no difference in CHF was observed between the Rydapt + chemotherapy and placebo + chemotherapy arms. In patients at risk, Rydapt should be used with caution and the patient closely monitored by assessing LVEF when clinically indicated (at baseline and during treatment).

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

Pulmonary toxicity

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

Embryofoetal toxicity and breast-feeding

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

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

Paediatric patients

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

Severe renal impairment

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

Interactions

Caution is required when concomitantly prescribing 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 because they can increase the plasma concentrations of midostaurin especially when (re-)starting with midostaurin treatment (see section 4.5). Alternative medicinal products 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 midostaurin-related toxicity.

Excipients

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

This medicinal product contains 666 mg of alcohol (ethanol) in each 200 mg dose (maximum daily dose), which is equivalent to 14 vol. % ethanol anhydrous. The amount in a 200 mg dose of this medicine is equivalent to 17 ml beer or 7 ml wine. The small amount of alcohol in this medicine will not have any noticeable effects. Alcohol may be harmful in patients with alcohol-related problems, epilepsy or liver problems or during pregnancy or breast-feeding.

4.5. Interaction with other medicinal products and other forms of interaction

Midostaurin undergoes extensive hepatic metabolism mainly through CYP3A4 enzymes which are either 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 plasma concentrations of midostaurin and therefore the safety and/or efficacy of Rydapt.

Strong CYP3A4 inducers

Concomitant use of Rydapt with strong inducers of CYP3A4 (e.g. carbamazepine, rifampicin, enzalutamide, phenytoin, St. John's Wort [Hypericum perforatum]) is contraindicated (see section 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 CYP3A4 inducer rifampicin (600 mg daily) to steady state with a 50 mg single dose of midostaurin decreased midostaurin Cmax by 73% and AUCinf by 96% on average, respectively. CGP62221 exhibited a similar pattern. The mean AUClast of CGP52421 decreased by 60%.

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 50 mg midostaurin led to a significant increase in midostaurin exposure (1.8-fold Cmax increase and 10-fold AUCinf increase) and 3.5-fold increase in AUCinf of CGP62221, while the Cmax of the active metabolites (CGP62221 and CGP52421) decreased by half (see section 5.2). At steady state of midostaurin (50 mg twice daily for 21 days), with the strong CYP3A4 inhibitor itraconazole at steady state in a subset of patients (N=7), midostaurin steady-state exposure (Cmin) was increased by 2.09-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 multiple doses of midostaurin (50 mg twice daily) at steady state decreased bupropion AUCinf and AUClast by 48% and 49% respectively and Cmax by 55% compared to administration of bupropion alone. This indicates that midostaurin is a mild inducer of CYP2B6. Medicinal products with a narrow therapeutic range that are substrates of CYP2B6 (e.g. bupropion or efavirenz) should be used with caution when administered concomitantly with midostaurin, and may need dose adjustment to maintain optimal exposure.

Based on in-vitro data, midostaurin and its active metabolites, CGP52421 and CGP62221, are inhibitors of CYP1A2 and CYP2E1 and inducers of CYP1A2. Therefore, medicinal products with a narrow 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, and may 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 single dose 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 rosuvastatin alone. This indicates that midostaurin has a mild inhibitory effect on BCRP substrates. Medicinal products with a narrow therapeutic range that are substrates of the transporter BCRP (e.g. rosuvastatin or atorvastatin) should be used with caution when administered concomitantly with midostaurin, and may need dose adjustment to maintain optimal exposure.

Hormonal contraceptives

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

Food interactions

In healthy subjects, 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 (see section 5.2).

Rydapt is recommended to be administered with food.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Women of childbearing potential should be informed that animal studies show midostaurin to be harmful to the developing foetus. Sexually active women of childbearing potential are advised to have a pregnancy test within 7 days prior to starting treatment with Rydapt and that they 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.

Pregnancy

Midostaurin can cause foetal 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 foetotoxicity (see section 5.3). Rydapt is not recommended during pregnancy or in women of childbearing potential not using contraception. Pregnant women should be advised of the potential risk to the foetus.

Breast-feeding

It is unknown whether midostaurin or its active metabolites are excreted in human milk. Available animal 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 after stopping treatment.

Fertility

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

4.7. Effects on ability to drive and use machines

Rydapt has minor influence on the ability to drive and use machines. Dizziness and vertigo have been reported in patients taking Rydapt and should be considered when assessing a patient's ability to drive or use machines.

4.8. Undesirable effects

Summary of the safety profile

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 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 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 were haemoglobin 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 ANC decreased (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 most frequent 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 versus 1.3% in the placebo arm. The most frequent Grade 3/4 adverse reaction leading to discontinuation in the 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 the maintenance phase (single agent Rydapt or placebo) was assessed separately, a difference in the type and severity of ARs was observed. The overall incidence of ARs during the maintenance phase was generally 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 more often in the midostaurin arm versus placebo during maintenance included: nausea (46.4% versus 17.9%), 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 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 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 Rydapt arm 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 median duration 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 frequent non-haematological laboratory abnormalities were hyperglycaemia (93.7%), total bilirubin increased (40.1%), lipase increased (39.4%), aspartate aminotransferase (AST) increased (33.8%), and alanine aminotransferase (ALT) increased (33.1%), while the most frequent haematological laboratory abnormalities were absolute lymphocyte count decreased (73.2%) and ANC decreased (58.5%). The most 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 most frequent 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 are ranked 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 available data). Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness.

AML

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

Table 3 Adverse reactions observed in AML

Adverse reaction

All grades

Grades 3/4

Frequency category

Rydapt + chemo

n=2291

%

Rydapt + chemo

n=3451

%

Infections and infestations

Device-related infection

24

15.7

Very common

Upper respiratory tract infection

5.2

0.6

Common

Neutropenic sepsis

0.9

3.5

Uncommon

Blood and lymphatic system disorders

Febrile neutropenia

83.4

83.5

Very common

Petechiae

35.8

1.2

Very common

Lymphopenia

16.6

20

Very common

Immune system disorders

Hypersensitivity

15.7

0.6

Very common

Metabolism and nutrition disorders

Hyperuricaemia

8.3

0.6

Common

Psychiatric disorders

Insomnia

12.2

0

Very common

Nervous system disorders

Headache

45.9

2.6

Very common

Syncope

5.2

4.6

Common

Tremor

3.9

0

Common

Eye disorders

Eyelid oedema

3.1

0

Common

Cardiac disorders

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

Respiratory, thoracic and mediastinal disorders

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

Gastrointestinal disorders

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

Skin and subcutaneous tissue disorders

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

Musculoskeletal and connective tissue disorders

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

General disorders and administration site conditions

Pyrexia

34.5

3.2

Very common

Catheter-related thrombosis

3.5

2

Common

Investigations

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 prolonged

12.7

2.6

Very common

Hypercalcaemia*

6.7

0.6

Common

Weight increased

6.6

0.6

Common

1For trial sites in North America, all grades were collected for 13 pre-specified adverse events. For all other adverse events, only grades 3 and 4 were collected. Therefore, all grade AEs are summarised only for patients in non-North American trial sites, whereas Grades 3 and 4 are summarised for patients in all trial sites.

2This AR was included after identification in the post-marketing setting. Interstitial lung disease has been derived from post-marketing experience with Rydapt via spontaneous case reports and literature cases. 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)

N=142

Frequency category

All grades

%

Grades 3/4

%

Infections and infestations

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

Blood and lymphatic system disorders

Febrile neutropenia

7.7

7.0

Common

Immune system disorders

Hypersensitivity

2.1

0

Common

Anaphylactic shock

0.7

0.7

Uncommon

Nervous system disorders

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

Vascular disorders

Hypotension

9.2

2.1

Common

Haematoma

6.3

0.7

Common

Respiratory, thoracic and mediastinal disorders

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

Gastrointestinal disorders

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

General disorders and administration site conditions

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

Investigations

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

Injury, poisoning and procedural complications

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.

Description of selected adverse reactions

Gastrointestinal disorders

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 to discontinuation in 4.2% of the patients. Most of the events occurred within the first 6 months of treatment and were managed with supportive prophylactic medicinal products.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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

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