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RYDAPT is a brand name for Midostaurin, supplied as a capsule. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: RYDAPT is indicated in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy for the treatment of adult patients with newly diagnosed FLT3- mutated acute myeloid leukemia (AML). A validated test is required to confirm the FLT3 mutation status of AML. RYDAPT is…
Verbatim from this product's HC label. Tap a section to expand.
1 Dosing considerations AML Prior to initiation of treatment with RYDAPT in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy, patients must have confirmation of FLT3 mutation (internal tandem duplication [ITD] or tyrosine kinase domain [TKD]) using a validated test.
Product Monograph Master Template Template Date:
September 2020 RYDAPT® (Midostaurin) Page 5 of 48 In patients receiving a hematopoietic stem cell transplant (SCT), RYDAPT should be discontinued prior to the conditioning regimen for SCT. 2 Recommended dose and dosage adjustment Recommended Dose in AML The recommended dose of RYDAPT is 50 mg twice daily on Days 8 to 21 of each cycle of induction with cytarabine and daunorubicin and on Days 8 to 21 of each cycle of consolidation with cytarabine.
Patients may be given up to 2 cycles of induction therapy with cytarabine and daunorubicin if complete remission is not observed at the end of the first induction cycle. Each induction cycle is a minimum of 24 days in duration. Patients who have residual AML after a second induction cycle should be discontinued from RYDAPT treatment.
Patients in complete remission after induction therapy should be given up to 4 cycles of consolidation therapy with cytarabine. Each consolidation cycle is a minimum of 28 days in duration and should begin within two weeks following hematologic recovery (ANC ≥ 1000/μL and platelet count ≥ 100,000/μL) but not sooner than 28 days from the beginning of the previous cycle.
Recommended Dose in ASM, SM-AHN, and MCL The recommended starting dose of RYDAPT is 100 mg twice daily. Treatment should be continued as long as clinical benefit is observed or until unacceptable toxicity occurs. Dosage Adjustment Dosage Adjustment in AML Recommended dosage adjustments for RYDAPT in patients with AML are provided in Table 1.
Table 1 - Recommended dose adjustments for RYDAPT (AML indication) Criteria RYDAPT dosing 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-hematological toxicities Interrupt RYDAPT until toxicities considered at least possibly related to RYDAPT have resolved to Grade ≤2, then resume RYDAPT. Dosage Adjustment in ASM, SM-AHN, and MCL Recommended dosage adjustments for RYDAPT in patients with ASM, SM-AHN, and MCL are provided in Table 2.
1 Adverse Reaction Overview AML In the phase III, randomized, double-blind, placebo controlled study of RYDAPT in patients with newly diagnosed FLT3-mutated AML, the most frequent (incidence ≥20%) adverse drug reactions (ADRs) in the RYDAPT plus standard chemotherapy arm were febrile neutropenia, nausea, exfoliative dermatitis, vomiting, stomatitis, headache, petechiae, pyrexia, epistaxis, hyperglycemia, back pain and device related infections.
The most frequent Grade 3/4 ADRs (incidence ≥10%) were febrile neutropenia, lymphopenia, device-related infection, and exfoliative dermatitis. 1% in the placebo plus standard chemotherapy arm. 9%). 3%). 2% in the placebo arm. 2%). ASM, SM-AHN, and MC In two single-arm, open-label, multicenter studies in patients with ASM, SM-AHN, or MCL, the most frequent ADRs (incidence ≥20%) were nausea, vomiting, diarrhea, peripheral edema, fatigue, constipation, pyrexia and headache.
The most frequent Grade 3/4 ADRs (incidence ≥5%) were fatigue, sepsis, pneumonia, febrile neutropenia, diarrhea, dyspnea, nausea and vomiting. 3% of patients. 6%). 3% of patients. The most frequent adverse events that led to dose modification (incidence ≥5%) were nausea, vomiting, electrocardiogram QT prolonged and neutropenia.
9% of patients. The most common adverse events leading to discontinuation (incidence ≥1%) were electrocardiogram QT prolonged, ascites, nausea, vomiting, febrile neutropenia, thrombocytopenia, amylase increased, pleural effusion, and acute myeloid leukaemia.
On-treatment deaths unrelated to the underlying malignancy occurred in 15 patients (11%), most commonly from infection (sepsis or pneumonia), followed by cardiac events. 2 Clinical Trial Adverse Reactions Clinical trials are conducted under very specific conditions.
The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.
General Drug-Drug Interactions Concomitant use of RYDAPT with drugs that strongly inhibit CYP3A4 can increase midostaurin exposure. Alternative medicinal products that do not strongly inhibit CYP3A4 activity should be considered. 4 Drug-drug Interactions).
Concomitant use of RYDAPT with drugs that strongly induce CYP3A4 can decrease midostaurin exposure. , carbamazepine, rifampin, St. 4 Drug-drug Interactions). Cardiovascular QTc Interval Prolongation An increased frequency of QT prolongation was noted in patients treated with RYDAPT in clinical trials Route of Administration Dosage Form / Strength/Composition Non-medicinal Ingredients Oral Capsule 25 mg All-rac-α-tocopherol (vitamin E), corn oil mono- di-triglycerides, ethanol anhydrous, gelatin, glycerol, iron oxide red, iron oxide yellow, macrogol 400, macrogolglycerol hydroxystearate, purified water, red pharmaceutical ink, titanium dioxide.
4 Abnormal laboratory findings, ECG Findings) and in the post-market setting. Particular care should be exercised when administering RYDAPT with a QTc- prolonging drug to patients who are suspected to be at an increased risk of experiencing torsade de pointes (see 7 WARNINGS AND PRECAUTIONS, Monitoring and Laboratory Tests).
4 Drug-drug Interactions). Cardiac dysfunction Patients with symptomatic congestive heart failure were excluded from clinical studies. In clinical studies with RYDAPT 100 mg twice daily (BID), events of cardiac failure, some of which were fatal, and decreases in left ventricular ejection fraction (LVEF) occurred.
Patients should be assessed for signs and symptoms of heart failure at baseline and periodically during treatment with RYDAPT. In patients at risk, RYDAPT should be used with caution and patients should be closely monitored by assessing LVEF when clinically indicated (at baseline and during treatment).
4 Abnormal laboratory findings). 5 x 109/L) was generally reversible by withholding RYDAPT until recovery or discontinuation in the ASM, SM-AHN and MCL studies. White blood cells (WBCs) should be monitored regularly, especially at treatment initiation.
RYDAPT is contraindicated in patients with hypersensitivity to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
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5x 109/L, then resume RYDAPT at 50 mg twice daily, and if tolerated, gradually 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 if low platelet count persists for > 21 days and is suspected to be related to RYDAPT. Hemoglobin less than 8 g/dL attributed to RYDAPT in patients without MCL, or life- threatening anemia attributed to RYDAPT in patients with baseline hemoglobin value of 8 - 10 g/dL Interrupt RYDAPT until hemoglobin 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 if low hemoglobin 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 RYDAPT at 50 mg twice daily, and if tolerated, gradually increase to 100 mg twice daily.
Other Grade 3/4 non-hematological 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.
ANC:
Absolute Neutrophil Count CTCAE severity: Grade 1 = mild symptoms; 2 = moderate symptoms; 3 = severe symptoms; 4 = life-threatening symptoms. Special Populations Renal impairment No dosage adjustment is required for patients with mild or moderate renal impairment (creatinine clearance [CrCl] ≥30 mL/min).
Clinical experience in patients with severe renal impairment (CrCl 15 to 29 mL/min) is limited. No data are available in patients with end-stage renal disease.
Product Monograph Master Template Template Date:
September 2020 RYDAPT® (Midostaurin) Page 7 of 48 Hepatic impairment No dosage adjustment is required in patients with mild or moderate (Child-Pugh A or B) hepatic impairment. Limited data obtained from severe (Child-Pugh C) hepatic impairment subjects are insufficient to recommend dose adjustment.
5 × upper limit of normal were excluded from studies with RYDAPT in combination with chemotherapy. 5 x ULN or > 3 x ULN if disease- related. Pediatric patients (>18 years) Health Canada has not authorized an indication for the use of RYDAPT in the pediatric population.
3 Pharmacokinetics, Special Populations and Conditions) Geriatric patients No dosage adjustments are required in […]
AML The safety evaluation of RYDAPT (50 mg twice daily) in patients with newly diagnosed FLT3-mutated AML is based on a phase III, randomized, double-blind, placebo-controlled study. A total of 717 patients were randomized (1:1) to receive RYDAPT or placebo sequentially (on Days 8 to 21) in combination with standard daunorubicin (60 mg/m2 on Days 1 to 3) / cytarabine (200 mg/m2 on Days 1 to 7) induction and high dose cytarabine (3 g/m2 on Days 1, 3, 5) consolidation, followed by maintenance with continuous RYDAPT or placebo treatment according to initial assignment for up to 12 cycles (28 days/cycle).
5% of the study population were females. 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 was 11 months (16 to 520 days for patients in the RYDAPT arm, and 22 to 381 days in the placebo arm).
Table 4 presents the common ADRs reported in the phase III study in patients with newly diagnosed FLT3-mutated AML. 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.
The severity of ADRs was graded based on the Common Terminology Criteria for Adverse Event (CTCAE). Table 6 presents the laboratory abnormalities from the same phase III study in patients with newly diagnosed FLT3-mutated AML. Table 4 - Common Adverse Drug Reactions1 (≥ 10% Incidence) reported in the pivotal AML clinical study Adverse drug reactions All grades Grades 3/4 RYDAPT + chemo4 n=2292 % Placebo + chemo4 n=2262 % RYDAPT + chemo4 n=3452 % Placebo + chemo4 n=3352 % Blood and lymphatic system disorders Febrile neutropenia 83 81 84 83 Petechiae 36 27 1 <1 Lymphopenia3 17 19 20 23 Cardiac disorders Product Monograph Master Template Template Date: September 2020 RYDAPT® (Midostaurin) Page 14 of 48 Adverse drug reactions All grades Grades 3/4 RYDAPT + chemo4 n=2292 % Placebo + chemo4 n=2262 % RYDAPT + chemo4 n=3452 % Placebo + chemo4 n=3352 % Hypotension 14 15 6 3 Sinus tachycardia 10 8 1 0 Gastrointestinal disorders Nausea3 83 70 6 10 Vomiting3 61 53 3 5 Stomatitis 22 14 4 3 Abdominal pain upper 17 15 0 <1 Hemorrhoids 15 11 1 0 General disorders and administration site conditions Pyrexia 35 35 3 3 Immune system disorders Hypersensitivity 16 14 <1 1 Infections and infestations Device related infection 24 17 16 10 Investigations Hyperglycemia3 20 17 7 5 Electrocardiogram QT prolonged5 20 17 6 5 Activated […]
In ASM, SM-AHN, and MCL studies, on-treatment deaths unrelated to the underlying malignancy occurred in 15 patients (11%), most commonly from infection (sepsis or pneumonia). 5 x 109/L in patients with ASM, SM-AHN and MCL, as recommended in Tables 5 and 6.
2 Recommended dose and dosage adjustment, Dosage Adjustment). Any active serious infections should be under control prior to starting treatment with RYDAPT monotherapy. 2 Recommended Dose and Dosage Adjustment, Dosage Adjustment). Monitoring and Laboratory Tests WBCs should be monitored regularly, especially at treatment initiation (see 7 WARNINGS AND PRECAUTIONS, Hematologic).
Patients should be monitored for signs and symptoms of infection, including any device-related infections, at baseline and periodically during treatment with RYDAPT (see 7 WARNINGS AND PRECAUTIONS, Hematologic). Patients should be assessed for signs and symptoms of heart failure at baseline and periodically during Product Monograph Master Template Template Date: September 2020 RYDAPT® (Midostaurin) Page 10 of 48 treatment with RYDAPT.
In patients at risk, RYDAPT should be used with caution and patients should be closely monitored (at baseline and during treatment). 4 Abnormal laboratory findings, ECG Findings). 2 Recommended dose and dosage adjustment, Dosage Adjustment; 7 WARNINGS AND PRECAUTIONS, Respiratory).
Interval assessments of QT by ECG should be considered if RYDAPT is taken concurrently with medicinal products that can prolong the QT interval (see 7 WARNINGS AN PRECAUTIONS, Cardiovascular).
Reproductive Health:
Female and Male Potential Fertility There are no data on the effect of RYDAPT on human fertility. Based on findings in animals, RYDAPT may impair fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible (see 16 NONCLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology).
Teratogenic Risk Based on studies in animals, RYDAPT may cause fetal harm when administered to pregnant women and should not be used during pregnancy.
Pregnancy testing:
Sexually-active females of reproductive potential should be advised to have a pregnancy test within 7 days prior to starting treatment with RYDAPT.
Contraception:
Females of reproductive […]