Midostaurin

Name: Midostaurin

Brand names

  • Rydapt®

Adverse Effects

>10% (AML)

Nausea (83%)

Febrile neutropenia (83%)

Hypocalcemia (74%)

Increased ALT, all grades (71%)

Mucositis (66%)

Vomiting (61%)

Headache (46%)

Petechiae (36%)

Musculoskeletal pain (33%)

Epistaxis (28%)

Device-related infection (24%)

Hypernatremia (21%)

Upper respiratory tract infection (20%)

Hyperglycemia (20%)

Increased ALT, grades 3 and 4 (20%)

Hemorrhoids (15%)

Arthralgia (14%)

Hyperhidrosis (14%)

Prolonged aPTT (13%)

Renal insufficiency (12%)

Insomnia (12%)

>10% (SM)

Nausea (82%)

Hyperglycemia (80%)

Vomiting (68%)

Lymphopenia (66%)

Leukopenia (61%)

Anemia (60%)

Diarrhea (54%)

Thrombocytopenia (50%)

Neutropenia (49%)

Edema (40%)

Increased alkaline phosphatase (39%)

Hypocalcemia (39%)

Lipase increased (37%)

Hyperuricemia (37%)

Increased GGT (35%)

Musculoskeletal pain (35%)

Hyponatremia (34%)

Increased AST (32%)

Increased ALT (31%)

Fatigue (34%)

Abdominal pain (34%)

Upper respiratory tract infection (30%)

Hyperbilirubinemia (29%)

Hypoalbuminemia (27%)

Pyrexia (27%)

Constipation (29%)

Headache (26%)

Hypokalemia (25%)

Increased creatinine (25%)

Hyperkalemia (23%)

Dyspnea (23%)

Hypophosphatemia (22%)

Increased amylase (20%)

Hypomagnesemia (20%)

Arthralgia (19%)

Cough (18%)

Urinary tract infection (16%)

GI hemorrhage (14%)

Rash (14%)

Dizziness (13%)

Pleural effusion (13%)

Epistaxis (12%)

QT prolonged (11%)

Insomnia (11%)

Renal insufficiency (11%)

1-10% (AML)

Hyperuricemia (8%)

Hypertension (8%)

Cellulitis (7%)

Fungal infection (7%)

Dry skin (7%)

Weight increased (7%)

Pleural effusion (6%)

Thrombosis (5%)

Tremor (4%)

Pericardial effusion (4%)

Hypercalcemia (3%)

Eyelid edema (3%)

1-10% (SM)

Pneumonia (10%)

Herpes virus infection (10%)

Sepsis (9%)

Hypotension (9%)

Febrile neutropenia (8%)

Disturbance in attention (7%)

Tremor (6%)

Hematoma (6%)

Cardiac failure (6%)

Bronchitis (6%)

Dyspepsia (6%)

Weight increased (6%)

Contusion (6%)

Cellulitis or erysipelas (5%)

Vertigo (5%)

Chills (5%)

Oropharyngeal pain (4%)

Myocardial infarction or ischemia (4%)

Hypersensitivity (4%)

Mental status changes (4%)

Pulmonary edema (3%)

Gastritis (3%)

Interstitial lung disease or pneumonitis (2%)

What should I discuss with my healthcare provider before taking midostaurin?

You should not use midostaurin if you are allergic to it.

To make sure midostaurin is safe for you, tell your doctor if you have ever had:

  • lung disease or breathing problems.

Midostaurin can harm an unborn baby or cause birth defects, whether the mother or father is taking this medicine.

  • If you are a woman, do not use midostaurin if you are pregnant. You may need to have a negative pregnancy test before starting this treatment. Use effective birth control to prevent pregnancy while you are using this medicine and for at least 4 months after your last dose.

  • If you are a man, use effective birth control if your sexual partner is able to get pregnant. An unborn baby can be harmed if a man fathers the child while he is using midostaurin. Keep using birth control for at least 4 months after your last dose.

  • Tell your doctor right away if a pregnancy occurs while either the mother or the father is taking midostaurin.

You should not breast-feed while using this medicine and for at least 4 months after your last dose.

Cautions for Midostaurin

Contraindications

Hypersensitivity to midostaurin or any of the excipients.1

Warnings/Precautions

Embryofetal Toxicity

Based on its mechanism of action and findings from animal reproduction studies, midostaurin may cause fetal harm when administered to pregnant women. In animal studies, midostaurin caused embryofetal toxicities, including late embryofetal death and reduced fetal birth weight, with delays in fetal growth at doses lower than the recommended human dose. Advise pregnant women of the potential risk to the fetus. Verify the pregnancy status of females of reproductive potential within 7 days prior to initiating midostaurin therapy. Advise females of reproductive potential to use effective contraception during treatment with midostaurin and for at least 4 months after the last dose. Advise males with female partners to use effective contraception during treatment with midostaurin and for at least 4 months after the last dose.1

Pulmonary Toxicity

Cases of interstitial lung disease and pneumonitis, some fatal, have occurred in patients treated with midostaurin as monotherapy or with chemotherapy. Monitor patients for pulmonary symptoms. Discontinue midostaurin in patients who experience signs or symptoms of interstitial lung disease or pneumonitis without an infectious etiology.1

Specific Populations

Pregnancy

Risk Summary: Based on mechanism of action and findings in animal reproduction studies, midostaurin may cause fetal harm when administered to a pregnant woman. There are no available data on midostaurin use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, oral administration of midostaurin to pregnant rats and rabbits during organogenesis caused embryofetal toxicities, including late embryofetal death and reduced fetal birth weight, with delays in fetal growth at doses lower than the recommended human dose. Advise pregnant women of the potential risk to a fetus.1

The background risk of major birth defects and miscarriage for the indicated population are unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.1

Animal Data: When midostaurin was administered to female rats prior to mating and through the first week of pregnancy at a dose of 60 mg/kg/day (approximately 0.1 times the human exposure at the recommended dose based on AUC), there were increases in pre- and post-implantation loss, including total litter loss, resulting in a reduction in the number of live embryos.1

During organogenesis, midostaurin administered at oral doses greater than or equal to 3 mg/kg/day (approximately 0.004 times the human exposure at the recommended dose by AUC) to pregnant female rats caused late embryofetal death. Dilated lateral brain ventricles were observed in offspring of rats given doses greater than or equal to 3 mg/kg/day. Extra rib and reduced fetal birth weight with effects on fetal growth (severe renal pelvic cavitation and widened anterior fontanelle) were observed in the absence of maternal toxicity at the highest dose of 30 mg/kg/day (approximately 0.05 times the human exposure at the recommended dose by AUC). Midostaurin administered orally to pregnant rabbits during organogenesis led to maternal toxicity with spontaneous abortions and some delay in fetal growth (reduced fetal birth weight) at doses greater than or equal to 10 mg/kg/day (approximately 0.01 times the human exposure at the recommended dose by AUC).1

In an oral pre- and postnatal development study in the rat, adverse effects upon maternal performance included dams with signs of dystocia and a lower live litter size at 30 mg/kg/day (approximately 0.05 times the human exposure at the recommended dose by AUC). For the F1 offspring, lower body weights, accelerated complete eye opening and delayed auricular startle ontogeny were noted at 30 mg/kg/day.1

Lactation

There are no data on the presence of midostaurin or its active metabolites in human milk, the effect on the breastfed infant, or the effect on milk production. Orally administered midostaurin and its active metabolites pass into the milk of lactating rats within 1 hour of a 30 mg/kg/day dose, with approximately 5 times more in the milk of lactating rats compared to plasma.

Because of the potential for serious adverse reactions in breastfed infants from midostaurin, advise women not to breastfeed during treatment with midostaurin and for at least 4 months after the last dose.1

Females And Males of Reproductive Potential

Pregnancy testing is recommended for females of reproductive potential within seven days prior to initiating midostaurin.1

Midostaurin may cause fetal harm when administered to a pregnant woman Advise females of reproductive potential to use effective contraception during treatment with midostaurin and for at least 4 months after the last dose.1

Males with female sexual partners of reproductive potential should use effective contraception during midostaurin treatment and for at least 4 months after stopping treatment with midostaurin.1

Based on findings in animals, midostaurin may impair fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.1

Pediatric Use

Safety and effectiveness of midostaurin have not been established in pediatric patients.1

Geriatric Use

Of the 142 patients with advanced SM in clinical studies of midostaurin, 64 (45%) were aged 65 and over, and 16 (11%) were aged 75 years and over. No overall differences in safety or response rate were observed between the subjects aged 65 and over compared with younger subjects. Greater sensitivity of older individuals cannot be ruled out.1

Clinical studies in AML with midostaurin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.1

In general, administration for elderly patients should be cautious, based on patient’s eligibility for concomitant chemotherapy and reflecting the greater frequency of concomitant disease or other drug therapy.1

Common Adverse Effects

  • AML: The most common adverse reactions (≥20%) were febrile neutropenia, nausea, mucositis, vomiting, headache, petechiae, musculoskeletal pain, epistaxis, device-related infection, hyperglycemia, and upper respiratory tract infection.1

  • ASM, SM-AHN, or MCL: The most common adverse reactions (≥20%) were nausea, vomiting, diarrhea, edema, musculoskeletal pain, abdominal pain, fatigue, upper respiratory tract infection, constipation, pyrexia, headache, and dyspnea.1

Actions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

  • Strong CYP3A4 Inhibitors: Strong CYP3A4 inhibitors may increase exposure to midostaurin and its active metabolites. Consider alternative therapies that do not strongly inhibit CYP3A4 or monitor for increased risk of adverse reactions.1

  • Strong CYP3A4 Inducers: Avoid concomitant use as strong CYP3A4 inducers decrease exposure to midostaurin and its active metabolites.1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling (Patient Information).1

  • Pulmonary Adverse Reactions: Inform patients to seek medical attention for new cough, chest discomfort, or shortness of breath.1

  • Gastrointestinal Adverse Reactions: Inform patients that midostaurin can cause nausea, vomiting, and diarrhea. Advise patients to contact their healthcare provider if these symptoms occur or are persisting despite supportive medications.1

  • Embryofetal Toxicity: Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with midostaurin and for at least 4 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy.1

    Advise male patients with female partners of reproductive potential to use effective contraception during treatment with midostaurin and for at least 4 months after the last dose.1

  • Lactation: Advise women not to breastfeed during treatment with midostaurin and for at least 4 months after the final dose.1

  • Infertility: Advise females and males of reproductive potential that midostaurin may impair fertility.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Midostaurin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, liquid-filled

25 mg

Rydapt

Novartis

Uses of Midostaurin

  • It is used to treat a type of leukemia.
  • It is used to treat mastocytosis.

If OVERDOSE is suspected

If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Use Labeled Indications

Acute myeloid leukemia, FLT3-positive: Treatment of adult patients with newly diagnosed FLT3 mutation-positive (as detected by an approved test) acute myeloid leukemia (AML), in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy

Limitations of use: Not indicated as single-agent induction therapy for the treatment of patients with AML.

Mast cell leukemia: Treatment of adult patients with mast cell leukemia (MCL)

Systemic mastocytosis: Treatment of adult patients with aggressive systemic mastocytosis (ASM) or systemic mastocytosis with associated hematological neoplasm (SM-AHN)

Drug Interactions

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Conivaptan: May increase the serum concentration of Midostaurin. Management: Seek alternatives to the concomitant use of midostaurin and conivaptan if possible. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions. Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Midostaurin. Avoid combination

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Midostaurin. Management: Seek alternatives to the concomitant use of midostaurin and strong CYP3A4 inhibitors if possible. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

DilTIAZem: May increase the serum concentration of Midostaurin. Management: Seek alternatives to the concomitant use of midostaurin and diltiazem if possible. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions. Consider therapy modification

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Grapefruit Juice: May increase the serum concentration of Midostaurin. Management: Seek alternatives to the concomitant use of midostaurin and grapefruit juice if possible. If concomitant use cannot be avoided, monitor patients for increased risk of adverse reactions Consider therapy modification

Highest Risk QTc-Prolonging Agents: Moderate Risk QTc-Prolonging Agents may enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Hydroxychloroquine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

MiFEPRIStone: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Moderate Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Probucol: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Promazine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

St John's Wort: May decrease the serum concentration of Midostaurin. Avoid combination

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Vinflunine: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Avoid combination

Xipamide: May enhance the QTc-prolonging effect of Moderate Risk QTc-Prolonging Agents. Monitor therapy

Pregnancy Considerations

Adverse events were observed in animal reproduction studies with doses providing less than the human exposure at the recommended dose based on AUC. Based on the mechanism of action, midostaurin may cause fetal harm if used in pregnant women.

Pregnancy status should be verified within 7 days prior to therapy initiation. Females of reproductive potential and males with female partners of reproductive potential should use effective contraception during therapy and for at least 4 months after the last dose. Based on animal data, treatment with midostaurin may impair fertility in males and females.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Signs of infection like fever, chills, very bad sore throat, ear or sinus pain, cough, more sputum or change in color of sputum, pain with passing urine, mouth sores, or wound that will not heal.
  • Signs of skin infection like oozing, heat, swelling, redness, or pain.
  • Signs of high blood sugar like confusion, feeling sleepy, more thirst, more hungry, passing urine more often, flushing, fast breathing, or breath that smells like fruit.
  • Signs of kidney problems like unable to pass urine, change in how much urine is passed, blood in the urine, or a big weight gain.
  • Signs of electrolyte problems like mood changes, confusion, muscle pain or weakness, a heartbeat that does not feel normal, seizures, not hungry, or very bad upset stomach or throwing up.
  • Signs of bleeding like throwing up blood or throw up that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; vaginal bleeding that is not normal; bruises without a reason or that get bigger; or any bleeding that is very bad or that you cannot stop.
  • Flushing.
  • Chest pain.
  • Pinpoint red spots on the skin.
  • Sweating a lot.
  • Swelling.
  • A heartbeat that does not feel normal.
  • Very bad dizziness or passing out.
  • Not able to focus.
  • Shakiness.
  • Feeling very tired or weak.
  • Very bad and sometimes deadly lung problems have happened with this drug. Call your doctor right away if you have lung or breathing problems like trouble breathing, shortness of breath, or a cough that is new or worse.
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