Sotauric 25 Mg Capsules

SOTAURIC is indicated:

• in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation chemotherapy, and for patients in complete response followed by SOTAURIC 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).

Treatment with SOTAURIC should be initiated by a medical practitioner 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

SOTAURIC 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 SOTAURIC is 50 mg orally twice daily. SOTAURIC is administered on days 8 - 21 of induction and consolidation chemotherapy cycles, and then, for patients in complete response, maintenance therapy with SOTAURIC daily as single medicine, until relapse or for up to 12 cycles of 28 days each (see section 4.1). In patients receiving a haematopoietic stem cell transplant (SCT), SOTAURIC should be discontinued 48 hours prior to the conditioning regimen for SCT.

ASM, SM-AHN and MCL

The recommended starting dose of SOTAURIC is 100 mg orally twice daily. Treatment should be continued as long as clinical benefit is observed or until unacceptable toxicity occurs.

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. Johnu2019s Wort (Hypericum perforatum), carbamazepine, enzalutamide, phenytoin (see section 4.5).

Cardiovascular disorders: Congestive cardiac failure NYHA class III or IV; left ventricular ejection fraction (LVEF) < 50 %; myocardial infarction within the previous 6 months; heart block of any degree; congenital or acquired prolongation of QT time; poorly controlled hypertension.

Neutropenia and infections

Neutropenia has occurred in patients receiving SOTAURIC as monotherapy and in combination with chemotherapy (see section 4.8). Severe neutropenia (ANC < 0,5 x 109/L) was generally reversible by withholding SOTAURIC 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 SOTAURIC should be interrupted until ANC is u2265 1,0 x 109/L, as recommended in Tables 1 and 2. SOTAURIC should be discontinued in patients who develop recurrent or prolonged severe neutropenia that is suspected to be related to SOTAURIC (see section 4.2).

Cardiac dysfunction

Patients with symptomatic congestive heart failure were excluded from clinical studies (see section 4.3). 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 SOTAURIC + chemotherapy and placebo + chemotherapy arms. In patients at risk, SOTAURIC 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 (see section 4.3). Caution is warranted in patients at risk of QTc prolongation (e.g. due to concomitant medicines and/or electrolyte disturbances). Interval assessments of QT by ECG should be considered if SOTAURIC is taken concurrently with medicines that can prolong QT interval (see sections 4.3).

Pulmonary toxicity

Interstitial lung disease (ILD) and pneumonitis, in some cases fatal, have occurred in patients treated with SOTAURIC monotherapy or in combination with chemotherapy. Patients should be monitored for pulmonary symptoms indicative of ILD or pneumonitis and SOTAURIC discontinued in patients who experience pulmonary symptoms indicative of ILD or pneumonitis without an infectious aetiology that are u2265 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 SOTAURIC and to use effective contraception during treatment with SOTAURIC and for at least 4 months after stopping treatment. Because of the potential for serious adverse reactions in breast-feeding infants from SOTAURIC, women should discontinue breast-feeding during treatment with SOTAURIC and for at least 4 months after stopping treatment (see section 4.6).

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).

Caution is advised with the concomitant use of SOTAURIC with medicines 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 medicines 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

SOTAURIC contains macrogolglycerol hydroxystearate, which may cause stomach discomfort and diarrhoea. A 100 mg dose of SOTAURIC contains approximately 14 vol. % ethanol anhydrous, which corresponds to 333 mg alcohol. This is equivalent to 8,4 ml beer or 3,5 ml wine. Alcohol may be harmful in patients with alcohol-related problems, epilepsy or liver problems or during pregnancy or breast-feeding.

SOTAURIC is contraindicated in pregnancy and lactation. 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 SOTAURIC and that they should use effective contraception (methods that result in less than 1 % pregnancy rates) when using SOTAURIC and for at least 4 months after stopping treatment with SOTAURIC.

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 fetotoxicity (see section 5.3). SOTAURIC should not be used during pregnancy or in women of childbearing potential not using contraception (see section 4.3). 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 SOTAURIC and for at least 4 months after stopping treatment.

Fertility

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

SOTAURIC has minor influence on the ability to drive and use machines. Dizziness and vertigo have been reported in patients taking SOTAURIC and should be considered when assessing a patientu2019s ability to drive or use machines.

Summary of the safety profile

AML

The safety evaluation of SOTAURIC (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 SOTAURIC plus standard chemotherapy arm versus 34 days (range 1 to 465 days) for patients in the placebo plus standard chemotherapy arm.

The most frequent adverse drug reactions (ADRs) in the SOTAURIC 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 ADRs 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 AEs occurred at similar rates in patients in the SOTAURIC versus the placebo arm. The most frequent serious AE in both arms was febrile neutropenia (16 %). Discontinuation due to any adverse reaction occurred in 3,1 % of patients in the SOTAURIC arm versus 1,3 % in the placebo arm. The most frequent Grade 3 / 4 adverse reaction leading to discontinuation in the SOTAURIC arm was exfoliative dermatitis (1,2 %).

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.