Rydapt

Last reviewed on RxList: 4/30/2021
Rydapt Side Effects Center

Medical Editor: John P. Cunha, DO, FACOEP

What Is Rydapt?

Rydapt (midostaurin) capsules are a kinase inhibitor indicated for the treatment of adult patients with Newly diagnosed acute myeloid leukemia (AML) that is FLT3 mutation-positive as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation. Rydapt is not indicated as a single-agent induction therapy for the treatment of patients with AML. Rydapt is also indicated for treatment of aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL).

What Are Side Effects of Rydapt?

Common side effects of Rydapt include:

Dosage for Rydapt

The dose of Rydapt to treat AML is 50 mg orally twice daily with food. The dose of Rydapt to treat ASM, SM-AHN, and MCL is 100 mg orally twice daily with food.

What Drugs, Substances, or Supplements Interact with Rydapt?

Rydapt may interact with:

  • boceprevir,
  • clarithromycin,
  • cobicistat,
  • conivaptan,
  • danoprevir,
  • ritonavir,
  • diltiazem,
  • elvitegravir,
  • grapefruit juice,
  • idelalisib,
  • indinavir,
  • itraconazole,
  • ketoconazole,
  • lopinavir,
  • nefazodone,
  • nelfinavir,
  • paritaprevir,
  • ombitasvir and/or dasabuvir,
  • posaconazole,
  • saquinavir,
  • tipranavir,
  • troleandomycin,
  • voriconazole,
  • carbamazepine,
  • enzalutamide,
  • mitotane,
  • phenytoin,
  • rifampin, and
  • St. John's wort

Tell your doctor all medications and supplements you use.

Rydapt During Pregnancy and Breastfeeding

Rydapt is not recommended for use during pregnancy; it may harm a fetus. It is unknown if Rydapt passes into breast milk. Because of the potential for serious adverse reactions in breastfed infants, women are advised not to breastfeed during treatment with Rydapt and for at least 4 months after the last dose.

Additional Information

Our Rydapt (midostaurin) Capsules Side Effects Drug Center provides a comprehensive view of available drug information on the potential side effects when taking this medication.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

QUESTION

What is leukemia? See Answer
Rydapt Consumer Information

Get emergency medical help if you have signs of an allergic reaction: hives, warmth, redness, or tingly feeling; chest pain, difficult breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

  • pain or sores in or around your mouth, redness inside your mouth, sore throat;
  • sudden chest pain or discomfort, wheezing, dry cough, feeling short of breath;
  • high blood sugar--increased thirst, increased urination, dry mouth, fruity breath odor; or
  • low blood cell counts--fever, chills, tiredness, mouth sores, skin sores, easy bruising, unusual bleeding, pale skin, cold hands and feet, feeling light-headed or short of breath.

Common side effects may include:

  • fever, flu-like symptoms;
  • mouth sores;
  • unusual bleeding or bruising;
  • cold symptoms such as stuffy nose, sneezing, sore throat;
  • trouble breathing;
  • nausea, vomiting, stomach pain, constipation, diarrhea;
  • muscle or bone pain;
  • headache, feeling tired; or
  • swelling.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Read the entire detailed patient monograph for Rydapt (Midostaurin Capsules)

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Rydapt Professional Information

SIDE EFFECTS

The following serious adverse reactions are described elsewhere in the labeling:

  • Pulmonary Toxicity [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Acute Myeloid Leukemia

The safety evaluation of RYDAPT (50 mg twice daily with food) in patients with newly diagnosed FLT3 mutated AML is based on a randomized, double-blind, trial of RYDAPT (n = 345) or placebo (n = 335) with chemotherapy [see Clinical Studies]. The overall median duration of exposure was 42 days (range 2 to 576 days) for patients in the RYDAPT plus chemotherapy arm versus 34 days (range 1 to 465 days) for patients in the placebo plus chemotherapy arm. On the RYDAPT plus chemotherapy arm, 35% of patients completed induction and consolidation therapy, compared to 25% of patients on the placebo plus chemotherapy arm.

The most frequent (incidence greater than or equal to 20%) adverse drug reactions (ADRs) in the RYDAPT plus chemotherapy arm were febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia, and upper respiratory tract infections. The most frequent Grade 3/4 adverse reactions (incidence ≥ 10%) were febrile neutropenia, device-related infection and mucositis.

The most frequent serious adverse reaction (≥ 10%) in patients in the RYDAPT plus chemotherapy arm was febrile neutropenia (16%), which occurred at a similar rate in the placebo arm (16%).

Discontinuation due to any adverse reaction occurred in 9% of patients in the RYDAPT arm versus 6% in the placebo arm. The most frequent (> 1%) Grade 3/4 adverse reactions leading to discontinuation in the RYDAPT arm was renal insufficiency (1%).

Excluding deaths due to disease progression, no fatal adverse reactions occurred in the study. Overall, the most frequent non-treatment related cause of death in the RYDAPT plus chemotherapy arm was sepsis (2%) and occurred at a similar rate in the placebo arm (2%).

Table 2 presents the frequency category of adverse reactions reported in the randomized trial in patients with newly diagnosed FLT3 mutated AML. Adverse reactions are listed according to body system. Within each body system, the adverse reactions are ranked by frequency, with the most frequent reactions first. Table 3 presents the key laboratory abnormalities from the same randomized trial in patients with newly diagnosed FLT3 mutated AML.

Table 2: Common Adverse Reactions (≥ 10% Incidence and ≥ 2% More Frequent on the Midostaurin Arm) of Patients With Acute Myeloid Leukemia in Study 1

Adverse Reactions All Grades Grades ≥ 3
RYDAPT + chemo
n = 2291
%
Placebo + chemo
n = 2261
%
RYDAPT + chemo
n = 3451
%
Placebo + chemo
n = 3351
%
Gastrointestinal disorders
  Nausea 83 70 6 10
  Mucositisa 66 62 11 13
  Vomiting 61 53 3 5
  Hemorrhoids 15 11 1 0
Blood and lymphatic system disorders
  Febrile neutropenia 83 81 84 83
  Petechiae 36 27 1 1
Nervous system disorders
  Headachea 46 38 3 3
Musculoskeletal and connective tissue disorders
  Musculoskeletal paina 33 31 5 2
  Arthralgia 14 8 <1 <1
Respiratory, thoracic and mediastinal disorders
  Epistaxis 28 24 3 1
Infections and infestations
  Device-related infection 24 17 16 10
  Upper respiratory tract infectiona 20 15 4 3
Investigations
  Hyperglycemiaa 20 17 7 6
  Activated partial thromboplastin time prolonged 13 8 3 2
Skin and subcutaneous tissue disorders
  Hyperhidrosis 14 8 0 0
Renal and urinary disorders
  Renal insufficiencya 12 9 5 3
Psychiatric disorders
  Insomnia 12 8 0 <1
1For trial sites in North America, only Grades 3 and 4 were collected.
aGrouped terms:
  • Upper respiratory tract infections: e.g., nasopharyngitis, upper respiratory tract infections, sinusitis.
  • Mucositis: e.g., radiation mucositis, stomatitis, laryngeal pain.
  • Musculoskeletal pain: e.g., back pain, bone pain, pain in extremity.
  • Renal insufficiency: e.g., blood creatinine increased, renal failure, acute kidney injury.
  • Hyperglycemia: mainly hyperglycemia.

Other notable adverse reactions occurring in < 10% of patients treated with RYDAPT but at least 2% more frequently than in the placebo group included:

  • Infections and infestations: Cellulitisa (7%), fungal infectiona (7%)
  • Metabolism and nutrition disorders: Hyperuricemia (8%)
  • Nervous system disorders: Tremor (4%)
  • Eye disorders: Eyelid edema (3%)
  • Cardiac disorders: Hypertensiona (8%), pericardial effusion (4%)
  • Respiratory, thoracic and mediastinal disorders: pleural effusion (6%)
  • Skin and subcutaneous tissue disorders: Dry skin (7%)
  • General disorders and administration site conditions: Thrombosisa (5%)
  • Investigations: Weight increased (7%), hypercalcemia (3%)

aGrouped terms:

  • Thrombosis: e.g., thrombosis in device, thrombosis.
  • Cellulitis: e.g., cellulitis, erysipelas.
  • Fungal infection: e.g., Bronchopulmonary aspergillosis, pneumonia fungal, splenic infection fungal, hepatic candidiasis.

Table 3: New or Worsening Laboratory Abnormalities (≥ 10% Incidence and ≥ 2% More Frequent on the Midostaurin Arm) Reported in Patients With Acute Myeloid Leukemia on Study 1

Laboratory Abnormality RYDAPT
(50 mg twice daily)
N = 345
All Grades
%
RYDAPT
(50 mg twice daily)
N = 345
Grade 3/4
%
Placebo
N = 335
All Grades
%
Placebo
N = 335
Grade 3/4
%
Alanine aminotransferase increased 71 20 69 16
Hypernatremia 21 1 15 2
Hypocalcemia 74 7 70 8

In Study 1, 205 patients (120 in RYDAPT arm and 85 in placebo arm) who remained in remission following completion of consolidation continued to receive either single agent RYDAPT or placebo for a median of 11 months (range 0.5 to 17 months) with 69 in the RYDAPT arm and 51 in the placebo completing 12 treatment cycles. Common adverse reactions (greater than or equal to 5% difference between the RYDAPT and placebo arms) reported for these patients included nausea (47% vs 18%), hyperglycemia (20% vs 13%) and vomiting (19% vs 5%).

Systemic Mastocytosis

Two single-arm, open-label multicenter trials (Study 2 and Study 3) evaluated the safety of RYDAPT (100 mg twice daily with food) as a single agent in 142 adult patients total with ASM, SM-AHN, or MCL. The median age was 63 (range 24 to 82), 63% had an ECOG performance status of 0 or 1, and 75% had no hepatic impairment (bilirubin and AST ≤ ULN) at baseline. The median duration of exposure to RYDAPT was 11.4 months (range 0 to 81 months), with 34% treated for ≥ 24 months.

The most frequent adverse reactions (≥ 20%), excluding laboratory terms, were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea (Table 4). Grade≥ 3 adverse reactions reported in ≥ 5%, excluding laboratory terms, were fatigue, sepsis, gastrointestinal hemorrhage, pneumonia, diarrhea, febrile neutropenia, edema, dyspnea, nausea, vomiting, abdominal pain, and renal insufficiency (Table 4).

Adverse reactions led to dose modifications (interruption or reduction) in 56% of patients. Among these, the most frequent adverse reactions (> 5%) were gastrointestinal symptoms, QT prolongation, neutropenia, pyrexia, thrombocytopenia, gastrointestinal hemorrhage, lipase increase, and fatigue. The median time to first dose modification for toxicity was 1.6 months, with 75% of dose modifications first occurring within 5 months of starting treatment.

Treatment discontinuation due to adverse reactions occurred in 21% of patients. The most frequent adverse reactions causing treatment discontinuation included infection, nausea or vomiting, QT prolongation, and gastrointestinal hemorrhage.

Serious adverse reactions were reported in 68% of patients, most commonly (≥ 20%) due to infections and gastrointestinal disorders.

On-treatment deaths unrelated to the underlying malignancy occurred in 16 patients (11%), most commonly from infection (sepsis or pneumonia), followed by cardiac events. Of the on-treatment deaths from disease progression, 4 were also attributable to infection.

Table 4 summarizes the adverse reactions reported in ≥ 10% of the patients with advanced SM.

Table 4: Adverse Reactions Reported in ≥ 10% of Patients With Advanced Systemic Mastocytosis (Study 2 and Study 3)

Adverse Reactiona RYDAPT (100 mg twice daily)
N = 142
All Grades
%
Grade ≥ 3
%
Gastrointestinal disorders
  Nausea 82 6
  Vomiting 68 6
  Diarrheaa 54 8
  Abdominal paina 34 6
  Constipation 29 <1
  Gastrointestinal hemorrhagea 14 9
General disorders and administration site conditions
  Edemaa 40 7
  Fatiguea 34 9
  Pyrexia 27 4
Infections and infestations
  Upper respiratory tract infectiona 30 1
  Urinary tract infectiona 16 3
  Pneumoniaa 10 8
  Herpesvirus infectiona 10 1
Musculoskeletal and connective tissue disorders
  Musculoskeletal paina 35 4
  Arthralgia 19 2
Nervous system disorders
  Headachea 26 1
  Dizziness 13 0
Respiratory, thoracic and mediastinal disorders
  Dyspneaa 23 7
  Cougha 18 <1
  Pleural effusion 13 4
  Epistaxis 12 3
Skin and subcutaneous disorders
  Rasha 14 3
Investigations
  QT prolonged 11 <1
Psychiatric disorders
  Insomnia 11 0
Renal disorders
  Renal insufficiencya 11 5
Toxicity was graded per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.
Represents adverse reactions, excluding laboratory terms, occurring up to 28 days after last midostaurin dose, regardless of baseline grade.
aGrouped terms:
  • Upper respiratory tract infection: e.g., nasopharyngitis, upper respiratory tract infections.
  • Urinary tract infection: e.g., urinary tract infection, cystitis.
  • Pneumonia: e.g., pneumonia, lung infection.
  • Herpesvirus infection: e.g., oral herpes, herpes zoster.
  • Headache: e.g., headache, sinus headache.
  • Dyspnea: e.g., dyspnea, bronchospasm, respiratory failure.
  • Cough: e.g., cough, productive cough.
  • Diarrhea: e.g., diarrhea, gastroenteritis, colitis.
  • Abdominal pain: e.g., abdominal pain, abdominal pain upper.
  • Gastrointestinal hemorrhage: e.g., gastrointestinal hemorrhage, hemorrhoidal hemorrhage, duodenal ulcer hemorrhage.
  • Fatigue: e.g., fatigue, asthenia.
  • Rash: e.g., rash, rash maculo-papular, erythema multiforme.
  • Musculoskeletal pain: e.g., back pain, musculoskeletal pain, pain in extremity.
  • Renal insufficiency: e.g., blood creatinine increased, renal failure, acute kidney injury.
  • Edema: e.g., edema, edema peripheral.

Gastrointestinal Toxicities Leading to Treatment Modification

In patients with advanced SM, the median time to onset of nausea was 9 days, with 75% of cases beginning within the first 3 months. The median time to onset of vomiting was 1 month.

Other clinically significant adverse reactions occurring in ≤ 10% of patients included:

Infections and infestations: Sepsis (9%)a, bronchitis (6%), cellulitis or erysipelas (5%)

Blood and lymphatic system disorders: Febrile neutropenia (8%)

Cardiac disorders: Cardiac failure (6%), myocardial infarction or ischemia (4%)a

Immune system disorders: Hypersensitivity (4%)a

Nervous system disorders: Disturbance in attention (7%), tremor (6%), mental status changes (4%)

Ear and labyrinth disorders: Vertigo (5%)

Vascular disorders: Hypotension (9%), hematoma (6%)

Respiratory, thoracic and mediastinal disorders: Oropharyngeal pain (4%), interstitial lung disease or pneumonitis (2%), pulmonary edema (3%)a

Gastrointestinal disorders: Dyspepsia (6%), gastritis (3%)a

General disorders and administration site conditions: Chills (5%)

Investigations: Weight increased (6%)

Injury, poisoning and procedural complications: Contusion (6%)

aGrouped terms:

  • Sepsis: e.g., sepsis, staphylococcal/Enterobacter/Escherichia sepsis
  • Hypersensitivity: includes one report of anaphylactic shock
  • Myocardial infarction or ischemia: e.g., myocardial infarction and acute myocardial infarction, angina pectoris
  • Gastritis: gastritis, gastritis erosive, gastritis hemorrhagic
  • Pulmonary edema: pulmonary edema, pulmonary congestion

Table 5 summarizes new or worsening laboratory abnormalities. Common (≥ 10%) Grade 3 or higher non-hematologic laboratory abnormalities were hyperglycemia (non-fasting), lipase increase, and hyperuricemia. The most common (≥ 20%) Grade 3 or higher hematologic laboratory abnormalities were lymphopenia, anemia, thrombocytopenia, and neutropenia. Grade 4 hematologic abnormalities occurring in ≥ 5% were thrombocytopenia (13%), neutropenia (8%), anemia (6%), and lymphopenia (6%).

Table 5: Most Common (≥ 20%) New or Worsening Laboratory Abnormalities Reported in Patients With Advanced Systemic Mastocytosis (Study 2 and Study 3)

Test RYDAPT (100 mg twice daily)
N = 142
All Grades
%
Grade ≥ 3
%
Hematology
  Lymphopenia 66 42
  Leukopenia 61 19
  Anemia 60 38
  Thrombocytopenia 50 27
  Neutropenia 49 22
Chemistry
  Hyperglycemiaa 80 18
  Alk phos increase 39 9
  Hypocalcemia 39 2
  Lipase increase 37 18
  Hyperuricemia 37 11
  GGT increaseb 35 9
  Hyponatremia 34 5
  AST increase 32 3
  ALT increase 31 4
  Hyperbilirubinemia 29 4
  Hypoalbuminemia 27 1
  Hypokalemia 25 6
  Creatinine increase 25 <1
  Hyperkalemia 23 4
  Hypophosphatemia 22 1
  Amylase increase 20 7
  Hypomagnesemia 20 0
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyltransferase.
Includes abnormalities occurring up to 28 days after last midostaurin dose, if new or worsened from baseline or if baseline was unknown.
aNon-fasting.
bAmong 116 evaluable patients.

DRUG INTERACTIONS

Effect Of Strong Cytochrome P450 (CYP) 3A Inhibitors And Inducers

Table 6 lists the potential effects of the coadministration of strong CYP3A modulators on RYDAPT.

Table 6: Drug Interactions With RYDAPT That Affect Midostaurin

Strong CYP3A Inhibitors
Clinical Impact
  • Coadministration of RYDAPT with strong CYP3A inhibitors may increase midostaurin concentrations. The increase in midostaurin concentrations may be pronounced if strong CYP3A inhibitors are administered during the first week of RYDAPT administration [see CLINICAL PHARMACOLOGY].
  • Increased midostaurin concentrations may increase the risk of toxicity.
Prevention or Management
  • Consider alternative therapies that do not strongly inhibit CYP3A activity.
  • Alternatively, with coadministration of RYDAPT and strong CYP3A inhibitors, monitor patients for increased risk of adverse reactions, especially during the first week of consecutive RYDAPT administration in advanced SM population, and during first week of RYDAPT administration in each cycle of chemotherapy in AML population.
Examples Boceprevir, clarithromycin, cobicistat, conivaptan, danoprevir and ritonavir, diltiazem, elvitegravir and ritonavir, grapefruit juicea, idelalisib, indinavir and ritonavir, itraconazole, ketoconazole, lopinavir and ritonavir, nefazodone, nelfinavir, paritaprevir and ritonavir and (ombitasvir and/or dasabuvir), posaconazole, ritonavir, saquinavir and ritonavir, tipranavir and ritonavir, troleandomycin, voriconazole
Strong CYP3A Inducers
Clinical Impact
  • Coadministration of RYDAPT with strong CYP3A inducers may decrease midostaurin concentrations [see CLINICAL PHARMACOLOGY].
  • Decreased midostaurin concentrations may reduce efficacy.
Prevention or Management Avoid coadministration of RYDAPT with strong CYP3A4 inducers.
Examples Carbamazepine, enzalutamide, mitotane, phenytoin, rifampin, St. John’s wortb
aThe effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation was used (e.g., high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation was used (e.g., low dose, single strength).
bThe induction potency of St. John’s wort may vary widely based on preparation.

Read the entire FDA prescribing information for Rydapt (Midostaurin Capsules)

© Rydapt Patient Information is supplied by Cerner Multum, Inc. and Rydapt Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

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