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midostaurin
Midostaurin is a tyrosine kinase inhibitor that targets multiple receptors (including FLT3, KIT kinase). It inhibits FLT3 receptor signaling in leukemic cells that express internal tandem duplication (ITD) and tyrosine kinase domain (TKD) mutant receptors or overexpressing wild type receptors, inducing cell cycle arrest and apoptosis. Midostaurin inhibits the wild type and D816V mutant KIT, interfering with KIT signaling and inhibits cell proliferation and survival, and histamine release in mast cells. It also binds to the catalytic domain of multiple kinases (PDGF-R, VEGFR2, etc.) to inhibit cell growth.
| Time to reach steady state | 28 days |
| Effects with food |
AUC ↑ by 22% with standard meal and 59% with high-fat meal. Cmax ↓ by 20% with standard meal and 27% with high fat meal. Time to peak concentration was increased with food as compared to fasting. In trials, midostaurin was administered with a meal to reduce toxicity. |
| Peak plasma levels |
1-3 hours (fasted state) 2.5-3 hours (with standard or high-fat meal) |
| PPB |
> 98% (mainly alpha-1-acid glycoprotein) |
| Cross blood brain barrier? |
Yes- animal studies |
Midostaurin undergoes extensive hepatic metabolism through CYP3A4 enzymes.
| Active metabolites |
CGP62221 and CGP52421 (28% and 38% of total plasma exposure) |
| Half-life |
Median terminal T1/2 of midostaurin, CGP62221 and CGP52421 = 21, 32, and 471 hours respectively |
| Feces |
78%; 73% as metabolites |
| Urine |
4% |
- Acute myeloid leukemia (AML)
- Systemic mastocytosis (SM)
- Mast cell leukemia (MCL)
Refer to the product monograph for a full list and details of approved indications.
Emetogenic Potential:
The following table lists adverse effects that occurred in the phase III study in patients with newly diagnosed FLT3-mutated AML in the midostaurin + chemotherapy arm. Only adverse effects that occurred at a frequency of >2% compared to the placebo + chemotherapy arm are listed. It also includes severe, life-threatening and post-marketing adverse effects from other sources. Adverse effects marked with “^” were observed in SM and MCL monotherapy, open-label studies.
| ORGAN SITE | SIDE EFFECT* (%) | ONSET** | |||
|---|---|---|---|---|---|
| Cardiovascular | Arrhythmia (10%) (sinus tachycardia; 1% severe) | E | |||
| Cardiotoxicity (rare) | E | ||||
| Hypertension (8%) (may be severe) | E | ||||
| Hypotension (6%) (severe) | E | ||||
| Pericardial effusion (4%) | E | ||||
| QT interval prolonged (20%) (6% severe) | E | ||||
| Thromboembolism (4%) (catheter-related) | E | ||||
| Dermatological | Exfoliative Dermatitis (62%) (14% severe) | E | |||
| Hyperhidrosis (14%) | E | ||||
| Gastrointestinal | Abdominal pain (17%) | E | |||
| Constipation (29%) ^ | E | ||||
| Diarrhea (51%) ^ | E | ||||
| Dyspepsia (6%) ^ | E | ||||
| Hemorrhoids (15%) | E | ||||
| Mucositis (22%) | E | ||||
| Nausea, vomiting (83%) (6% severe) | E | ||||
| General | Edema - limbs (35%) ^ | E | |||
| Fatigue (31%) ^ | E | ||||
| Hematological | INR / prothrombin time increased (13%) (activated partial thromboplastin time) | E | |||
| Myelosuppression ± infection, bleeding (84%) (may be severe) | E | ||||
| Hepatobiliary | ↑ LFTs (9%) (ALT, AST) (severe) | E | |||
| Hypersensitivity | Hypersensitivity (16%) (<1% severe) | I E | |||
| Metabolic / Endocrine | Hyperglycemia (20%) (may be severe) | E | |||
| Hyperuricemia (8%) | E | ||||
| Musculoskeletal | Musculoskeletal pain (22%) | E | |||
| Nervous System | Confusion (6%) ^ | E | |||
| Headache (46%) | E | ||||
| Insomnia (12%) | E | ||||
| Syncope (5%) | E | ||||
| Tremor (4%) | E | ||||
| Ophthalmic | Eye disorders (7%) (keratitis, eyelid edema) | E | |||
| Respiratory | Acute respiratory distress syndrome (ARDS) (2%) | E | |||
| Cough, dyspnea (16%) ^ | E | ||||
| Interstitial lung disease (rare) | E | ||||
| Pharyngolaryngeal pain (12%) | E | ||||
| Pleural effusion (6%) | E | ||||
| Pneumonitis (11%) | E | ||||
* "Incidence" may refer to an absolute value or the higher value from a reported range.
"Rare"
may refer to events with < 1% incidence, reported in post-marketing, phase 1 studies,
isolated data or anecdotal
reports.
** I = immediate (onset in hours to days)
E = early (days to weeks)
D = delayed (weeks to months)
L = late (months to years)
The most common side effects for midostaurin include myelosuppression ± infection, bleeding, nausea, vomiting, diarrhea, headache, edema - limbs, fatigue, constipation, mucositis, musculoskeletal pain and hyperglycemia.
QT prolongation occurred at an increased frequency in patients on midostaurin. Caution in patients with suspected increased risk of torsade de pointes and if midostaurin is taken concomitantly with QTc interval-prolonging drugs.
Cardiac failure, including fatal cases and decreases in LVEF have been reported in trials of midostaurin 100mg bid.
Neutropenia and infection, including fatal cases, have been reported, including device-related infections. In the SM and MCL studies severe neutropenia (ANC less than 0.5 x 109/L) was generally reversible when midostaurin was withheld.
Pulmonary toxicity, including interstitial lung (ILD) disease and pneumonitis (fatal in some cases) have been reported.
Refer to protocol by which the patient is being treated.
-
Patients must have confirmation of FLT3 mutation with a validated test prior to starting AML induction treatment.
-
Midostaurin should be stopped prior to the administration of any HSCT conditioning regimens.
-
Use only in patients ≥ 60 years of age if they are eligible for intensive induction regimens and have adequate performance status and no significant comorbidities
-
Active serious infections should be under control prior to starting treatment with midostaurin monotherapy.
AML - Induction and Consolidation:
Oral: 50 mg BID on Days 8 to 21 of each chemotherapy cycle
Note:
- Midostaurin is given as part of induction with cytarabine and daunorubicin for up to 2 cycles of at least 24 days each if remission is not observed at the end of the first induction cycle.
- If complete remission, midostaurin is given with cytarabine consolidation therapy for up to 4 cycles (q 28 days minimum).
See CYTA(HD)+MIDO for the consolidation regimen details.
SM and MCL:
Oral: 100 mg BID
AML:
| Toxicity | Grade | Action |
| Pulmonary infiltrates | ≥ Grade 3 |
Hold for remainder of cycle. With recovery to ≤ grade 1, resume at same dose level. |
| Other non-hematological | ≥ Grade 3 |
Hold until recovery to ≤ grade 2*, then resume at same dose level. |
* toxicities considered at least possibly related to midostaurin
SM and MCL:
Dose Levels
| Dose Level | Midostaurin Dose (mg BID) |
| 0 | 100 |
| -1 | 50 |
Hematological Toxicities**
|
Toxicity |
Criteria |
Action |
|
Neutropenia |
ANC < 1 x 109/L (in patients without MCL) |
Hold until recovery to ≥ 1.5x 109/L. Resume at 1 dose level ↓. If tolerated, may ↑ 1 dose level. Discontinue if low ANC persists for > 21 days. |
|
ANC < 0.5 x 109/L (in patients with baseline ANC value of 0.5-1.5 x 109/L) |
||
|
Thrombocytopenia |
Platelets < 50 x 109/L (in patients without MCL) |
Hold until recovery to ≥ 50x 109/L. Resume at 1 dose level ↓. If tolerated, may ↑ 1 dose level. Discontinue if low platelet count persists for > 21 days. |
|
Platelets < 25 x 109/L (in patients with baseline platelet count of 25-75 x 109/L) |
||
|
Hemoglobin |
<80 g/L (in patients without MCL) |
Hold until recovery to ≥ 80 g/L. Resume at 1 dose level ↓. If tolerated, may ↑ 1 dose level. Discontinue if low hemoglobin persists for > 21 days. |
|
Life-threatening anemia in patients with baseline hemoglobin of 80 -100 g/L |
**Attributed to midostaurin
Nonhematologic Toxicities:
|
Toxicity |
Grade |
Action |
|
Nausea/vomiting |
≥ Grade 3^ |
Hold for 3 days (6 doses). Resume at 1 dose level ↓. If tolerated, may ↑ 1 dose level. |
|
Other non-hematological toxicities |
≥ Grade 3 |
Hold until recovery to ≤ grade 2. Resume at 1 dose level ↓. If tolerated, may ↑ 1 dose level. |
^Despite optimal antiemetic prophylaxis
| Hepatic Impairment | Midostaurin Dose |
| Mild or Moderate (Child-Pugh A or B) |
No dose adjustment needed |
|
Severe |
Caution (no data available) |
| Renal Impairment | Midostaurin Dose |
| Mild or Moderate (CrCl ≥ 30 mL/min) | No dose adjustment needed |
| Severe (CrCl 15-29 mL/min) |
Caution; data is limited. |
| End-stage renal disease | No data |
-
No dose adjustment required.
-
Clinical studies in SM and MCL demonstrated no overall differences in safety or response rate in patients ≥65 years of age compared to younger patients. Use with caution.
-
There is limited experience in patients 60-70 years of age and no experience in patients >70 years of age in AML studies. In an interim analysis, serious adverse effects and deaths were slightly higher in patients ≥65 years of age compared to younger patients.
No dose adjustment required. In population PK analysis, gender did not have clinically meaningful effects on clearance.
No dose adjustment based on ethnicity required. No differences in PK profile was shown between Caucasian and Black patients. In healthy Japanese volunteers, PK profiles of midostaurin and metabolites are similar compared to PK studies in Caucasians and Black patients.
There are limited data in pediatric patients and the safety and efficacy of midostaurin has not been established. Cases of markedly delayed hematological recoveries were reported in pediatric patients after the second induction chemotherapy cycle with midostaurin.
-
Midostaurin should be taken orally, twice daily, approximately 12 hours apart.
-
Administer with food to help prevent nausea. Prophylactic antiemetics may be necessary.
-
Capsules should be swallowed whole with a glass of water and not opened, crushed, or chewed.
-
If a dose is missed, it should be skipped and the next scheduled dose taken at the scheduled time.
-
If vomiting occurs, no additional dose should be taken and the next scheduled dose should be taken at the scheduled time.
-
Grapefruit, starfruit, Seville oranges, their juices or products during treatment should be avoided.
-
Store in the original package at room temperature (not above 30ºC).
-
Keep out of reach and sight of children and pets.
- In patients with hypersensitivity to midostaurin or to any components of the formulation.
-
Patients with total bilirubin ≥ 2.5 × ULN were excluded from AML trials.
-
SM and MCL trials excluded patients with serum creatinine > 20 mg/L, LFTs > 2.5 x ULN or > 5 x ULN if disease-related and total bilirubin > 1.5 x ULN or > 3 x ULN if disease-related.
-
Caution in patients with increased risk for torsade de pointes and with concomitant QTc interval-prolonging drugs. SM and MCL trials excluded patients with a baseline QTcF> 450ms.
-
Caution in patients at risk for heart failure. Patients with symptomatic congestive heart failure were excluded from clinical studies.
-
Genotoxicity:
Yes
-
Mutagenicity:
No
-
Clastogenicity:
No
-
Fetotoxicity:
Yes
Animal studies demonstrated embryo-fetal toxicity.
Midostaurin is not recommended for use in pregnancy. If pregnancy is possible, adequate contraception should be used by both sexes during treatment and for at least 4 months after the last dose.
It is unknown if midostaurin reduces the effectiveness of hormonal contraceptives; a barrier method should also be used.
-
Excretion into breast milk:
Yes
Breastfeeding is not recommended during treatment and for at least 4 months after stopping treatment.
-
Fertility effects:
Probable
Midostaurin was associated with reproductive toxicity in both males and females in animal studies.
In vitro data shows that midostuarin may increase the exposure of drugs cleared by CYP2D6, CYP2E1, P-gp, BCRP or OATP 1B1 and decrease the exposure of co-administered drugs primarily cleared by CYP2B6 and CYP2C19.
The effect on drugs that are substrates of CYP1A2, CYP2C8 or CYP2C9 is uncertain.
| AGENT | EFFECT | MECHANISM | MANAGEMENT |
|---|---|---|---|
| CYP3A4 inhibitors (i.e. ketoconazole, clarithromycin, ritonavir, fruit or juice from grapefruit, Seville oranges or starfruit) | ↑ exposure to midostaurin and metabolite CGP62221 (ketoconazole increased midostaurin Cmax and AUC by 1.8- and 10.4-fold, respectively) | ↓ midostaurin metabolism | Avoid strong inhibitors. If strong inhibitors must be used concomitantly, closely monitor for toxicity, especially during the 1st week of each cycle. |
| Strong CYP3A4 inducers (i.e. rifampin, carbamazepine, St. John’s Wort, etc) | ↓ exposure to midostaurin and both active metabolites (rifampicin decreased midostaurin Cmax and AUC by 73% and 96% respectively) | ↑ midostaurin metabolism | Avoid |
| Drugs that may prolong QT (i.e. amiodarone, procainamide, sotalol, venlafaxine, amitriptyline, etc.) | ↑ risk of torsade de pointes | Additive | Caution; monitor closely |
| CYP3A4/5 substrates (e.g. cyclosporine, pimozide, tacrolimus, triazolo-benzodiazepines) | unknown | Caution with drugs with narrow therapeutic index | |
| CYP2D6, CYP2E1, P-gp, BCRP, BSEP or OATP1B1 substrates | ↑ substrate exposure | ↓ substrate metabolism | Caution with drugs with narrow therapeutic index |
| CYP2B6 and CYP2C19 substrates | ↓ substrate exposure | ↑ substrate metabolism | Caution with drugs with narrow therapeutic index |
| CYP1A2, CYP2C8 or CYP2C9 substrates | unknown | ↑/↓ substrate metabolism | Caution with drugs with narrow therapeutic index |
| Drugs that disrupt electrolyte levels (e.g. loop, thiazide, and related diuretics; laxatives and enemas; proton pump inhibitors; amphotericin B, high-dose corticosteroids) | Additive | Caution |
Treating physicians may decide to monitor more or less frequently for individual patients but should always consider recommendations from the product monograph.
| Monitor Type | Monitor Frequency |
|---|---|
CBC |
Baseline, before each cycle and as clinically indicated; more frequently at treatment initiation |
Liver function tests |
Baseline, before each cycle and as clinically indicated |
Renal function tests |
Baseline, before each cycle and as clinically indicated |
LVEF |
Baseline and as clinically indicated, especially if risk factors |
ECG |
Baseline and as clinically indicated if patient is concurrently taking drugs that can prolong QT interval |
Blood glucose |
Baseline, at each visit and as clinically indicated |
| Clinical toxicity assessment for signs and symptoms of infection, heart failure, dermatological, hypersensitivity, GI, hyperuricemia, and pulmonary symptoms | Baseline and at each visit |
Grade toxicity using the current NCI-CTCAE (Common Terminology Criteria for Adverse Events) version
| Monitor Type | Monitor Frequency |
|---|---|
INR, aPTT |
Baseline and at each visit |
Exceptional Access Program (EAP Website)
- midostaurin - First-line treatment of adult patients diagnosed with FLT3-mutated acute myeloid leukemia, in combination with specific standard induction followed by consolidation chemotherapy, according to clinical criteria
- Midostaurin (Inpatient) - FLT3-mutated Acute Myeloid Leukemia
Midostaurin (Rydapt®) Product Monograph. Novartis Pharmaceuticals Canada Inc. June 29, 2021.
Gotlib J, Kluin-Nelemans HC, George TI, et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. N Engl J Med. 2016;374(26):2530-2541. doi:10.1056/NEJMoa1513098
Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 2017; 377:454-464.
April 2022 Drug monograph revision
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