Midostaurin

Before taking midostaurin,

• tell your doctor and pharmacist if you are allergic to midostaurin, any other medications, or any of the ingredients in midostaurin capsules. Ask your pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, and nutritional supplements you are taking or plan to take. Be sure to mention any of the following: boceprevir (no longer available in the U.S.; Victrelis); carbamazepine (Carbatrol, Equetro, Tegretol, others); clarithromycin (Biaxin, in Prevpac); diltiazem (Cardizem, Cartia, Tiazac, others); enzalutamide (Xtandi); idelalisib (Zydelig); itraconazole (Onmel, Sporanox); ketoconazole (Nizoral); medications used to treat human immunodeficiency virus (HIV) such as cobicistat (Tybost, in Evotaz, in Genvoya, in Prezcobix, in Stribild), elvitegravir (Vitekta), indinavir (Crixivan), nelfinavir (Viracept), ritonavir (Norvir, in Kaletra, in Technivie, in Viekira), saquinavir (Invirase) and tipranavir (Aptivus); mitotane (Lysodren); nefazodone; phenytoin (Dilantin, Phenytek); posaconazole (Noxafil); rifampin (Rifadin, Rimactane, in Rifamate, in Rifater); troleandomycin (not available in the U.S.); and voriconazole (Vfend). Your doctor may need to change the doses of your medications or monitor you carefully for side effects. Many other medications may also interact with midostaurin, so be sure to tell your doctor about all the medications you are taking, even those that do not appear on this list.
• tell your doctor what herbal products you are taking, especially St. John's wort.
• tell your doctor if you have or have ever had an irregular heartbeat, QT prolongation (a heart problem that may cause irregular heartbeat, fainting, or sudden death), lung, liver, or kidney disease.
• tell your doctor if you are pregnant or plan to become pregnant. If you are a female, you should not become pregnant while you are taking midostaurin and for up to 4 months after your final dose. You will need to have a negative pregnancy test within 7 days before you start taking midostaurin. Talk to your doctor about birth control methods that will work for you. If you are male, you and your female partner should use birth control during your treatment and continue to use birth control for 4 months after your final dose. If you or your partner become pregnant while taking midostaurin, call your doctor immediately. Midostaurin may harm the fetus.
• tell your doctor if you are breastfeeding. You should not breastfeed while you are taking midostaurin and for 4 months after your final dose.
• you should know that this medication may decrease fertility in men and women.

Midostaurin may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away:

• nausea
• vomiting
• diarrhea
• headache
• nosebleeds
• tiredness
• weakness
• dizziness
• constipation
• hemorrhoids
• increased sweating
• stomach pain
• white patches or sores on the lips or in the mouth and throat
• swelling of the hands, feet, ankles, or lower legs
• back, bone, joint, limb, or muscle pain
• difficulty falling asleep or staying asleep

Some side effects can be serious. If you experience any of these symptoms, call your doctor immediately or get emergency medical treatment:

• fever, cough, sore throat, chills, and other signs of infection
• rapid, irregular, or pounding heartbeat
• shortness of breath
• chest pain
• flushing
• swelling of the lips, tongue, or throat
• difficulty breathing or swallowing
• hives
• rash
• itching
• new or worsening cough
• wheezing
• vomiting blood or vomiting material that looks like coffee grounds
• unusual bleeding or bruising
• burning or pain when urinating

Midostaurin may cause other side effects. Call your doctor if you have any unusual problems while taking this medication.

If you experience a serious side effect, you or your doctor may send a report to the Food and Drug Administration's (FDA) MedWatch Adverse Event Reporting program online (http://www.fda.gov/Safety/MedWatch) or by phone (1-800-332-1088).

Oral Administration

Take with food twice daily at ~12-hr intervals

Administer prophylactic antiemetics before treatment to reduce the risk of nausea and vomiting

Swallow capsules whole; do not open or crush capsules

Consider interval assessments of QT by ECG if coadministered with medications that can prolong the QT interval

Missed or vomited dose

• Do not make up the dose by taking another capsule
• Take the next dose at the usual scheduled time

Storage

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F)

Store in the original package to protect from moisture

Follow all directions on your prescription label. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Midostaurin is usually taken 2 times per day (once every 12 hours) with food.

Take your doses at regular intervals to keep a steady amount of the drug in your body at all times.

You may be given medication to prevent nausea or vomiting while you are taking midostaurin.

If you vomit shortly after taking midostaurin, do not take an extra dose. Wait until your next scheduled dose time to take the medicine again.

Do not crush or open a midostaurin capsule.

While using midostaurin, you may need frequent blood tests (every 1 to 4 weeks). Midostaurin is usually given until your body no longer responds to the medication.

Use all medications as directed by your doctor. Read the instructions provided with each medication. Do not change your doses or medication schedule without your doctor's advice.

Store midostaurin in the original container at room temperature, away from moisture and heat.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Use birth control to prevent pregnancy, whether you are a man or a woman. Midostaurin use by either parent may cause birth defects. Avoid pregnancy and breast-feeding for at least 4 months after you stop using this medicine.

Take the missed dose as soon as you remember. Skip the missed dose if it is almost time for your next scheduled dose. Do not take extra medicine to make up the missed dose.

Usual Adult Dose for Acute Myeloid Leukemia:

50 mg orally twice a day at approximately 12 hour intervals on Days 8 to 21 of each cycle of induction AND on Days 8 to 21 of each cycle of consolidation.

Comments:
-This drug is not indicated as a single-agent induction therapy for acute myeloid leukemia (AML) patients.
-Information on FDA-approved tests for the detection of FLT3 mutation in AML is available at: http://www.fda.gov/CompanionDiagnostics.

Use: In combination with standard cytarabine and daunorubicin induction and high-dose cytarabine consolidation, treatment of newly diagnosed AML who are FLT3 mutation-positive as detected by a FDA approved test.

Usual Adult Dose for Systemic Mastocytosis:

100 mg orally twice a day at approximately 12 hour intervals
Duration of Therapy: Until disease progression or unacceptable toxicity occurs.

Comments: Monitor for toxicity at least weekly for the first 4 weeks, every other week for the next 8 weeks, and monthly thereafter while on treatment.

Uses: Treatment of aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL).

Usual Adult Dose for Leukemia:

100 mg orally twice a day at approximately 12 hour intervals
Duration of Therapy: Until disease progression or unacceptable toxicity occurs.

Comments: Monitor for toxicity at least weekly for the first 4 weeks, every other week for the next 8 weeks, and monthly thereafter while on treatment.

Uses: Treatment of aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated hematological neoplasm (SM-AHN), or mast cell leukemia (MCL).

General

Midostaurin is available in the following dosage form(s) and strength(s):

Capsules: 25 mg.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

• AML: 50 mg orally twice daily with food.1

• ASM, SM-AHN, or MCL: 100 mg orally twice daily with food.1

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 midostaurin. 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.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this medicine, please talk with your doctor, nurse, pharmacist, or other health care provider.
• 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.

This information should not be used to decide whether or not to take midostaurin or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to midostaurin. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Review Date: October 4, 2017

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral:

Rydapt: 25 mg [contains cremophor rh40]

• Antineoplastic Agent, FLT3 Inhibitor
• Antineoplastic Agent, Tyrosine Kinase Inhibitor

Systemic mastocytosis (aggressive systemic mastocytosis, systemic mastocytosis with associated hematological neoplasm, or mast cell leukemia):

Hematologic toxicity (attributed to midostaurin):

ANC <1,000/mm3 (in patients without mast cell leukemia) or ANC <500/mm3 (in patients with baseline ANC of 500 to 1,500/mm3): Interrupt midostaurin; when ANC has improved to ≥1,000/mm3, resume therapy at a reduced dose of 50 mg twice daily and if tolerated, may increase dose to 100 mg twice daily.

Persistently low ANC for >21 days (associated with midostaurin): Discontinue midostaurin

Platelets <50,000/mm3 (in patients without mast cell leukemia) or platelets <25,000/mm3 (in patients with baseline platelet count of 25,000 to 75,000/mm3): Interrupt midostaurin; when platelets have improved to ≥50,000/mm3, resume therapy at a reduced dose of 50 mg twice daily and if tolerated, may increase dose to 100 mg twice daily.

Persistently low platelet count for >21 days (associated with midostaurin): Discontinue midostaurin

Hemoglobin <8 g/L (in patients without mast cell leukemia) or life-threatening anemia in patients with baseline hemoglobin of 8 to 10 g/L: Interrupt midostaurin; when hemoglobin has improved to ≥8 g/L, resume therapy at a reduced dose of 50 mg twice daily and if tolerated, may increase dose to 100 mg twice daily.

Persistently low hemoglobin for >21 days (associated with midostaurin): Discontinue midostaurin

Nonhematologic toxicity:

Nausea/vomiting, grade 3 or 4 (despite optimal antiemetic prophylaxis): Interrupt midostaurin for 3 days (6 doses), then resume therapy at a reduced dose of 50 mg twice daily. If tolerated, increase dose to 100 mg twice daily.

Other grade 3 or 4 toxicities: Interrupt midostaurin until improvement to ≤ grade 2, then resume therapy at a reduced dose of 50 mg twice daily. If tolerated, increase dose to 100 mg twice daily.

All indications: Pulmonary toxicity: Signs/symptoms of interstitial lung disease or pneumonitis without infectious etiology): Discontinue midostaurin.

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Store in the original package to protect from moisture.

Data not available.