Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
Rydapt is indicated:
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.
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.
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.
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 ¾ pulmonary infiltrates | Interrupt Rydapt for the remainder of the cycle. Resume Rydapt at the same dose when infiltrate resolves to Grade ≤1. |
| Other Grade ¾ 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 × 109/l) | Interrupt Rydapt until ANC ≥1.0 × 109/l, then resume at 50 mg twice daily. If neutropenia (ANC <1.0 × 109/l) persists >2 weeks and is suspected to be related to Rydapt, discontinue Rydapt. |
| Persistent Grade ½ 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
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.
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 × 109/l attributed to Rydapt in patients without MCL, or ANC less than 0.5 × 109/l attributed to Rydapt in patients with baseline ANC value of 0.5-1.5 × 109/l | Interrupt Rydapt until ANC ≥1.0 × 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 × 109/l attributed to Rydapt in patients without MCL, or platelet count less than 25 × 109/l attributed to Rydapt in patients with baseline platelet count of 25-75 × 109/l | Interrupt Rydapt until platelet count greater than or equal to 50 × 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 ¾ 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 ¾ 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.
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.
No dose adjustment is required in patients aged over 65 years (see section 5.2). There is limited experience with midostaurin 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.
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).
No dose adjustment is required in patients with mild or moderate (Child-Pugh A or B) hepatic impairment (see section 5.2). No study has been completed in patients with severe (Child-Pugh C) hepatic impairment (see section 4.4).
Rydapt has not been studied in patients with acute promyelocytic leukaemia and therefore its use is not recommended in this patient population.
The safety and efficacy of Rydapt in children and adolescents below 18 years have not been established (see section 5.1). Currently available data are described in section 5.2 but no recommendation on a posology can be made.
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.
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.
Shelf life: 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/Al/PVC-Al 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 local requirements.
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