Midostaurin

Based on in vitro data, midostaurin and/or its metabolites have the potential to inhibit CYP1A2, CYP2D6, CYP2C8, CYP2C9, CYP2E1 and CYP3A4/5 enzymes.

Based on in vitro data, midostaurin and/or its metabolites have the potential to induce CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19 and CYP3A4/5 enzymes. Midostaurin inhibited OATP1B1, BCRP and P-glycoprotein (P-gp) in vitro. The combination of data on in vivo midostaurin auto-induction upon repeated dosing and increase in plasma 4β-OH cholesterol levels suggest that midostaurin may be at least a moderate CYP3A4 inducer in vivo.

In vivo studies have not been conducted for the investigation of induction and inhibition of enzymes and transporters by midostaurin and the active metabolites. Medicinal products with a narrow therapeutic range that are substrates of CYP1A2 (e.g. tizanidine), CYP2D6 (e.g. codeine), CYP2C8 (e.g. paclitaxel), CYP2C9 (e.g. warfarin), CYP2C19 (e.g. omeprazole), CYP2E1 (e.g. chlorzoxazone), CYP3A4/5 (e.g. tacrolimus), CYP2B6 (e.g. efavirenz), P-gp (e.g. paclitaxel), BCRP (e.g. atorvastatin) or OATP1B1 (e.g. digoxin) should be used with caution when administered concomitantly with midostaurin and may need dose adjustment to maintain optimal exposure.

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 C_max increase and 10-fold AUC inf increase) and 3.5-fold increase in AUC_inf of CGP62221, while the C_max of the active metabolites (CGP62221 and CGP52421) decreased by half. 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 (C_min) was increased by 2.09-fold. C_min of CGP52421 was increased by 1.3-fold, whereas no significant effect in exposure of CGP62221 was observed.

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.

Caution is warranted when considering the administration of midostaurin in patients with severe hepatic impairment and patients should be carefully monitored for toxicity.

There are no data on the effect of midostaurin on human fertility. Animal studies with midostaurin have shown impaired fertility.

Neutropenia has occurred in patients receiving midostaurin as monotherapy and in combination with chemotherapy. Severe neutropenia (ANC <0.5 × 10⁹/l) was generally reversible by withholding midostaurin 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 midostaurin should be interrupted until ANC is ≥1.0 × 10⁹/l, as recommended. Midostaurin should be discontinued in patients who develop recurrent or prolonged severe neutropenia that is suspected to be related to midostaurin.

Interstitial lung disease (ILD) and pneumonitis, in some cases fatal, have occurred in patients treated with midostaurin monotherapy or in combination with chemotherapy. Patients should be monitored for pulmonary symptoms indicative of ILD or pneumonitis and midostaurin discontinued in patients who experience pulmonary symptoms indicative of ILD or pneumonitis that are ≥Grade 3 (NCI CTCAE).

Any active serious infection should be under control prior to starting treatment with midostaurin 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 midostaurin.

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 midostaurin + chemotherapy and placebo + chemotherapy arms. In patients at risk, midostaurin 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, 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 midostaurin is taken concurrently with medicinal products that can prolong QT interval.

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. Midostaurin 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.

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 midostaurin and for at least 4 months after stopping treatment.

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 midostaurin and that they should use effective contraception (methods that result in less than 1% pregnancy rates) when using midostaurin and for at least 4 months after stopping treatment with midostaurin. It is currently unknown whether midostaurin may reduce the effectiveness of hormonal contraceptives, and therefore women using hormonal contraceptives should add a barrier method of contraception.

Fertility

There are no data on the effect of midostaurin on human fertility. Animal studies with midostaurin have shown impaired fertility.

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

Summary of the safety profile

AML

The safety evaluation of midostaurin (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 midostaurin 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 midostaurin 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 midostaurin arm and 22 to 381 days in the placebo arm).

The most frequent adverse drug reactions (ADRs) in the midostaurin 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 ¾ 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 ¾ laboratory abnormalities were ANC decreased (85.8%), haemoglobin decreased (78.5%), ALT increased (19.4%) and hypokalaemia (13.9%).

Serious ADRs occurred at similar rates in patients in the midostaurin versus the placebo arm. The most frequent serious ADR in both arms was febrile neutropenia (16%).

Discontinuation due to any adverse reaction occurred in 3.1% of patients in the midostaurin arm versus 1.3% in the placebo arm. The most frequent Grade ¾ adverse reaction leading to discontinuation in the midostaurin arm was exfoliative dermatitis (1.2%).

Safety profile during maintenance phase

While Table 1 provides the incidence for ADRs over the total duration of the study, when the maintenance phase (single agent midostaurin or placebo) was assessed separately, a difference in the type and severity of ADRs was observed. The overall incidence of ADRs during the maintenance phase was generally lower than during the induction and consolidation phase. Incidences of ADRs were, however, higher in the midostaurin arm than in the placebo arm during the maintenance phase. ADRs 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 midostaurin or placebo in combination with chemotherapy. The most frequent Grade ¾ haematological abnormalities reported in patients during the maintenance phase with midostaurin were ANC decrease (20.8% versus 18.8%) and leukopenia (7.5% versus 5.9%).

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

ASM, SM-AHN and MCL

The safety of midostaurin (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 midostaurin was 11.4 months (range: 0 to 81 months).

The most frequent ADRs were nausea (82%), vomiting (68%), diarrhoea (51%), peripheral oedema (35%) and fatigue (31%). The most frequent Grade ¾ ADRs 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 ¾ 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 ADRs occurred in 31% of patients. The most frequent ADRs that led to dose modification (incidence ≥5%) were nausea and vomiting.

ADRs 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 drug reactions

ADRs are listed according to MedDRA system organ class. Within each system organ class, the ADRs are ranked by frequency, with the most frequent reactions first, 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 1 presents the frequency category of ADRs reported in the phase III study in patients with newly diagnosed FLT3-mutated AML.

Table 1. Adverse drug reactions observed in the AML clinical study:

¹ For 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.
* Frequency is based on laboratory values.

ASM, SM-AHN and MCL

Table 2 presents the frequency category of ADRs based on pooled data from two studies in patients with ASM, SM-AHN and MCL.

Table 2. Adverse drug reactions observed in the ASM, SM-AHN and MCL clinical studies:

* Frequency is based on laboratory values.

Description of selected adverse drug 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.