_
Please note that RYDAPT®▼ (midostaurin) is not subject to additional monitoring in Northern Ireland.
RYDAPT is indicated:1
- 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;
- 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)
If you are a healthcare professional in Great Britain, please click here to access the RYDAPT Summary of Product Characteristics for full safety information.
If you are a healthcare professional in Northern Ireland, please click here to access the RYDAPT Summary of Product Characteristics for full safety information.
The most frequent adverse drug reactions (ADRs) in the RYDAPT arm (n=229) 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%).1
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%).1
Summary of adverse reactions reported in AML clinical studies* and during post-marketing experience.1
Corresponding frequency category for each adverse event based on the 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).1
| Adverse drug reaction | All grades RYDAPT + chemo n=229† % |
Grades 3/4 RYDAPT + chemo n=345† % |
Frequency category |
|---|---|---|---|
| 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/Pneumonitis‡ | 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 dermatosis§ | - | - | 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 prolonged§ | 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 |
The most frequent adverse events reported for RYDAPT in studies of patients with ASM, SM-AHN and MCL (n=142) were nausea (82%), vomiting (68%), diarrhoea (51%), peripheral oedema (35%) and fatigue (31%).1
Adverse events that led to treatment discontinuation occurred in 9.2% of patients. The most frequent (incidence ≥1%) were febrile neutropenia, nausea, vomiting and pleural effusion.1
Summary of adverse reactions based on pooled data from two studies in patients with ASM, SM-AHN and MCL.1
Corresponding frequency category for each adverse event based on the 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).1
| Adverse drug 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 |
| Blood and lymphatic 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/Pneumonitis‡ | 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 prolonged¶ | 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 |
The recommended dose of RYDAPT for treatment of AML is 50 mg orally twice daily.1
The recommended starting dose of RYDAPT for treatment of ASM, SM-AHN and MCL is 100 mg orally twice daily.1
AML clinical study:
The safety evaluation of RYDAPT, in combination with standard chemotherapy, (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 (18–60 years of age).1
- Those who were in remission after consolidation therapy entered a maintenance phase in which they received either RYDAPT or placebo2
Serious adverse reactions occurred at similar rates in patients in the RYDAPT arm vs the placebo arm.2
The overall incidence of adverse reactions during the maintenance phase was generally lower than during the induction and consolidation phase. Incidences of adverse reactions were, however, higher in the RYDAPT arm than in the placebo arm during the maintenance phase.1
- No unexpected adverse events were reported2
- Few significant differences were observed between RYDAPT + SOC vs placebo + SOC in the rates of adverse events of grade 3, 4, or 5. These included:
- The rate of grade 3, 4, or 5 anaemia was higher with RYDAPT than with placebo (92.7% vs 87.8%, p=0.03)
- The rate of grade 3, 4, or 5 rash was higher with RYDAPT than with placebo (14.1% vs 7.6%, p=0.008)
- The rate of nausea was numerically higher in the placebo group than in the RYDAPT group (9.6% vs 5.6%, P=0.05 – not statistically significant)
The most frequent (incidence 30%) ADRs (all grades) in the RYDAPT plus standard intensive chemotherapy arm (n=229) were febrile neutropenia, nausea, exfoliative dermatitis, vomiting, headache, petechiae and pyrexia.1
The most frequent (incidence 10%) Grade 3/4 ADRs with RYDAPT plus standard intensive chemotherapy (n=355) were febrile neutropenia, lymphopenia, device-related infection and exfoliative dermatitis, hyperglycaemia and nausea.1
The incidence of grade ≥3 AEs was similar in the RYDAPT and placebo groups2
| Most common adverse events (Grade ≥3)1 |
RYDAPT + standard intensive chemotherapy (n=355) |
Placebo + standard intensive chemotherapy (n=354) |
p value |
|---|---|---|---|
| Number of patients (%) | |||
| Haematologic | |||
| Thrombocytopaenia | 346 (97) | 342 (97) | 0.52 |
| Neutropenia | 338 (95) | 339 (96) | 0.86 |
| Anaemia | 329 (93) | 311 (88) | 0.03 |
| Leukopenia | 93 (26) | 105 (30) | 0.32 |
| Lymphopenia | 68 (19) | 78 (22) | 0.35 |
| Non-haematologic | |||
| Febrile neutropenia | 290 (82) | 292 (82) | 0.84 |
| Infection | 186 (52) | 178 (50) | 0.60 |
| Lymphopenia | 68 (19) | 78 (22) | 0.35 |
| Diarrhoea | 56 (16) | 54 (15) | 0.92 |
| Hypokalaemia | 49 (14) | 60 (17) | 0.25 |
| Pain | 47 (13) | 44 (12) | 0.82 |
| Increased alanine aminotransferase | 45 (13) | 33 (9) | 0.19 |
| Rash or desquamation | 50 (14) | 27 (8) | 0.008 |
| Fatigue | 32 (9) | 37 (10) | 0.53 |
| Pneumonitis or pulmonary infiltrates | 28 (8) | 29 (8) | 0.89 |
| Nausea | 20 (6) | 34 (10) | 0.05 |
Adapted from Stone RM, et al. 2017.2
Not an exhaustive list of the AEs that occurred.
Special populations:1
Elderly (≥65 years)
No dose adjustment is required in patients aged over 65 years. There is limited experience with RYDAPT in AML patients aged 60–70 years and no experience in AML patients above 70 years. 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.
Hepatic impairment
No dose adjustment is required in patients with mild or moderate (Child-Pugh A or B) hepatic impairment. Exposure to RYDAPT and its active metabolite CGP62221 is substantially lower in patients with severe hepatic impairment than that in patients with normal hepatic function. 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).
Contraindications:1
Hypersensitivity to the active substance or to any of the following excipients:
Capsule content
- Macrogolglycerol hydroxystearate
- Macrogol
- Ethanol anhydrous
- Maize oil mono-di-triglycerides
- All-rac-alpha-tocopherol
Capsule shell
- Gelatin
- Glycerol
- Titanium dioxide (E171)
- Iron oxide yellow (E172)
- Iron oxide red (E172)
- Purified water
Printing ink
- Carmine (E120)
- Hypromellose
- Propylene glycol
Concomitant administration of potent CYP3A4 inducers, e.g. rifampicin, St. John’s Wort (Hypericum perforatum), carbamazepine, enzalutamide, phenytoin.
Special warnings and precautions for use:1
Neutropenia and infections
Neutropenia has occurred in patients receiving RYDAPT as monotherapy and in combination with chemotherapy. 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. 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. RYDAPT should be discontinued in patients who develop recurrent or prolonged severe neutropenia that is suspected to be related to RYDAPT.
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 CHF (including some fatalities) and transient decreases in 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 RYDAPT–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 RYDAPT is taken concurrently with medicinal products that can prolong QT interval.
Pulmonary toxicity
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 breastfeeding
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 breastfeeding infants from RYDAPT, women should discontinue breastfeeding during treatment with RYDAPT and for at least 4 months after stopping treatment.
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).
Severe renal impairment
Caution is warranted when considering the administration of RYDAPT in patients with severe renal impairment or end-stage renal disease and patients should be carefully monitored for toxicity.
Interactions
Caution is required when concomitantly prescribing with RYDAPT 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 RYDAPT especially when (re-)starting with RYDAPT treatment. 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 RYDAPT-related toxicity.
Not an exhaustive list of possible interactions. Please refer to section 4.5 of the Summary of Product Characteristics for the full information.
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 breastfeeding.
Fertility, pregnancy and lactation1
Women of childbearing potential
Women of childbearing potential should be informed that animal studies show RYDAPT 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
RYDAPT can cause foetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. 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.
Breastfeeding
It is unknown whether RYDAPT or its active metabolites are excreted in human milk. Breastfeeding 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 RYDAPT have shown impaired fertility.
Please refer to the RYDAPT Summary of Product Characteristics (SmPC) for full information before prescribing.
*The efficacy and safety of RYDAPT in combination with standard chemotherapy versus placebo plus standard chemotherapy and as single agent maintenance therapy was investigated in 717 patients (18 to 60 years of age) in a 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 receive RYDAPT 50 mg twice daily (n=360) or placebo (n=357) sequentially in combination with standard daunorubicin (60 mg/m2 daily on Days 1–3)/cytarabine (200 mg/m2 daily on Days 1–7) induction and high-dose cytarabine (3 g/m2 every 12 hours on Days 1, 3, 5) consolidation, followed by continuous RYDAPT or placebo treatment according to initial assignment for up to 12 additional cycles (28 days/cycle).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.1
‡This ADR 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.1
§This ADR was included after identification in the post-marketing setting.1
¶Frequency is based on laboratory values.1
‖SOC: A cycle was 28 days. Chemotherapy dosing during induction was cytarabine IV, 200 mg/m2/d on Days 1–7, and daunorubicin IV, 60 mg/m2/d on Days 1–3. During consolidation, high-dose cytarabine was given at a dose of 3 g/m2/d IV q12h on Days 1, 3 and 5.2
ADR, adverse drug reaction; AE, adverse event; ALT, alanine aminotransferase; AML, acute myeloid leukaemia; AMM, ANC, absolute neutrophil count; ASM, aggressive systemic mastocytosis; AST, aspartate aminotransferase; CHF, congenital heart failure; CIOMS, Council for International Organizations of Medical Sciences; CYP3A4, cytochrome P450 3A4; ECG, electrocardiogram; FLT, FMS-like tyrosine kinase; ILD, interstitial lung disease; IV, intravenous; LVEF, left ventricular ejection fraction; MCL, mast cell leukaemia; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; q12h, every 12 hours; QTc, corrected QT interval; SM-AHN, systemic mastocytosis with associated haematological neoplasm; SOC, standard of care; WBC, white blood count.
References
- RYDAPT (midostaurin) Summary of Product Characteristics.
- Stone RM, et al. N Engl J Med 2017;377(5):454–464.
